6-substituted phenoxychroman carboxylic acid derivatives

ABSTRACT

Compounds of Formula (I): in which A 1 , A 2 , W, L, G, R 7a , R 7b , R 8 , R 9  and R 10  have the meanings given in the specification, are DP2 receptor modulators useful in the treatment of immunologic diseases.

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising compounds of this invention, to a process formaking compounds of this invention and to the use of compounds of thisinvention in therapy. More particularly, this invention relates tocertain 6-substituted phenoxychroman carboxylic acid derivatives usefulin the treatment and prevention of allergic diseases such as asthma,allergic rhinitis and atopic dermatitis and other inflammatory diseasesmediated by prostaglandin D₂ (PGD₂).

DP2 is a G-protein coupled receptor that is selectively expressed oncell types that mediate allergic inflammation including mast cells,basophils, eosinophils and Th2 cells and there is growing evidence thatit plays a critical role in the pathophysiology of allergy (Hirai et.al., Journal of Experimental Medicine (2001) 193:255-261). Theendogenous ligands for DP2 (PGD2 and its active metabolites) are made byactivated mast cells and by Th2 cells, and can be readily detected atsites of allergic disease. Agonism of DP2 promotes the migration and oractivation of basophils, eosinophils and Th2 cells in vitro and in vivo(Kostenis and Ulven, Trends in Molecular Medicine (2006)12:1471-148-158), suggesting that this receptor may drive diseaseprocesses in vivo. In support of this mice made deficient in DP2 by geneinactivation through homologous recombination show evidence of reducedallergic responses in pre-clinical models of asthma and atopicdermatitis. Similar results have been reported using selective smallmolecule inhibitors of DP2 (reviewed in Pettipher, et. al., NatureReviews Drug Discovery (2007) 6:313-325).

Clinical validation for DP2 as a target for allergic disease is alsoprovided by Ramatroban (BAY u34505). Ramatroban was originally developedas a Thromboxane A2 (TP) receptor antagonist but showed unexpectedclinical activity in allergy, which could not be readily explained byits activity against TP. It has recently been shown that Ramatroban isalso an inhibitor of DP2 and its activity in pre-clinical models ofallergy can be recapitulated using selective inhibitors of DP2 but notof TP (Sugimoto et. al., Journal of Pharmacology and ExperimentalTherapeutics (2003) 305:347-352; Takeshiti et. al., InternationalImmunology (2004) 16:947-959). These findings support the view that theclinical efficacy seen with Ramatroban in allergic disease is due to itsactivity against DP2. Ramatroban is currently approved in Japan for thetreatment of seasonal allergic rhinitis. Based on the validation of DP2as a drug target in allergy many have sought to develop inhibitors ofDP2 for the treatment of allergic disease, and the first of these hasnow entered clinical development.

International patent application, publication number WO 2004/058164discloses inter alia, certain 2-substituted phenoxyphenylacetic acidderivatives that modulate the PGD₂-selective receptor CRTH2(chemoattractant receptor-homologous molecule expressed on Th2 cells),now more commonly referred to as DP2. The compounds are said to beuseful in the treatment of immunologic diseases such as asthma andallergic inflammation.

It has now been found that certain phenoxychroman carboxylic acidderivatives having an amide-linked group at the 4-position of thephenoxy moiety are DP2 receptor antagonists.

According to one aspect, the present invention provides a compound ofgeneral Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is hydrogen, CN, Cl, F, Br, OMe, (1-4C alkyl) or cyclopropyl;

A² is hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl;

W is —C(═O)NR¹— or —NR²C(═O)—;

R¹ and R² are each hydrogen or methyl;

L is a bond, —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, (2-4C)alkenylene,—O(1-4C alkyl)-*, -(1-4C alkyl)-O—*, -(1-4C alkyl)-S—*,(3-6C)cycloalkylene, or hetCyc¹, wherein the * indicates the point ofattachment to G, provided that when W is —C(═O)NR²— then L is not—(CH═CH)—;

m=0, 1 or 2;

n=0 or 1;

R^(a) and R^(b) are independently selected from hydrogen and (1-4Calkyl);

R³ is hydrogen, (1-4C alkyl) or CH₂OH;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen, (1-4C alkyl), OH, —O(1-4C alkyl) or F;

R⁶ is hydrogen, F or methyl,

or R⁵ and R⁶ together with the carbon to which they are attached form acyclopropyl ring,

provided that when m=0 and n=0, then R⁵ and R⁶ do not form a ring withthe carbon to which they are attached;

hetCyc¹ is a group having the formula

where t is 1 or 2 and p is 0 or 1, and the * indicates the point ofattachment to G;

G is Ar¹, Ar², naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from Cland OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2heteroatoms independently selected from O and N, a (3-6C)cycloalkyl ringoptionally substituted with one or more substituents independentlyselected from (1-4C)alkyl, an oxaspirononanyl ring, or t-butyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br, CF₃, (1-4C)alkyl, OH, —O(1-4Calkyl), —S(1-3C alkyl), —SCF₃, cyclopropyl, —CH₂N(1-3C alkyl)₂,—O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl-O-(1-3C)trifluoro alkyl,—OCH₂ (cyclopropyl), and (3-4C)alkynyl;

Ar² is phenyl which is substituted with Ar³, —O—Ar⁴, hetAr¹ or—O-hetAr², wherein Ar² is optionally further substituted with one ormore substituents independently selected from F, Cl and CF₃;

Ar³ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br and (1-4C alkyl);

Ar⁴ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br and (1-4C alkyl);

hetAr¹ is a 6-membered heteroaryl having 1-2 nitrogen atoms andoptionally substituted with one or more substituents independentlyselected from (1-4C alkyl);

hetAr² is a 6-membered heteroaryl having 1-2 nitrogen atoms andoptionally substituted with one or more substituents independentlyselected from (1-4C alkyl) and CF₃;

R^(7a), R^(7b) and R⁸ are each independently hydrogen or methyl;

R⁹ is hydrogen, methyl, fluoro or NO₂; and

R¹⁰ is hydrogen, methyl or fluoro.

Compounds according to the present invention have been found to be DP2antagonists and are useful in the treatment of immunologic diseases suchas asthma and allergic inflammation.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated in a mixture of isomers such as a racemic mixture,or in an enantiomerically pure form.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I.

Examples of salts of Formula I include alkali metal salts, such aslithium, sodium or potassium salts, or alkaline earth metal salts, suchas calcium salts. Particular mention is made of the sodium salt.

A further example of a salt includes a tromethamine salt (IUPAC name:2-amino-2-(hydroxymethyl)-1,3-propanediol; also known as Tris).

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention.

The term “(1-4C)alkyl” used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to four carbonatoms. Examples of alkyl groups include, but are not limited to, methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, and2-methyl-2-propyl.

The term “(2-4C)alkenylene” as used herein refers to a linear orbranched-chain bivalent hydrocarbon radical of two to four carbon atomshaving a double bond. The double bond may be in the cis- ortrans-orientation.

The term “(3-4C)alkynyl” as used herein refers to a linear orbranched-chain monovalent hydrocarbon radical of 3-4 carbons having atriple bond.

The term “(2-3C)fluoroalkyl” as used herein refers to a C₂-C₃ alkylgroup wherein one of the hydrogen atoms is replaced by a fluorine atom.

The term “(1-3C)difluoroalkyl” as used herein refers to a C₁-C₃ alkylgroup wherein two of the hydrogen atoms are each replaced by a fluorineatom.

The term “(1-3C)trifluoroalkyl” as used herein refers to a C₁-C₃ alkylgroup wherein three of the hydrogen atoms are each replaced by afluorine atom.

In certain embodiments, A¹ is CN, Cl, (1-4C alkyl) or cyclopropyl.

In certain embodiments, A¹ is CN, Cl, methyl or cyclopropyl.

In certain embodiments, A¹ is CN, Cl or cyclopropyl.

In certain embodiments, A¹ is CN or Cl.

In certain embodiments, A¹ is hydrogen. In certain embodiments, A¹ isCN. In certain embodiments, A¹ is Cl. In certain embodiments, A¹ is(1-4C alkyl). An example of A¹ is methyl. In certain embodiments, A¹ iscyclopropyl. In certain embodiments, A¹ is OMe. In certain embodiments,A¹ is Br.

In certain embodiments, A² is selected from H, Br, Cl, cyclopropyl andmethyl.

In certain embodiments, A² is selected from H, Br, Cl, and cyclopropyl.

In certain embodiments, A² is selected from hydrogen and Br.

In certain embodiments, A² is selected from hydrogen and Cl.

In certain embodiments, A² is selected from hydrogen and cyclopropyl.

In certain embodiments, A² is hydrogen. In certain embodiments, A² isCl. In certain embodiments, A² is Br. In certain embodiments, A² is(1-4C alkyl). A particular example is methyl. In certain embodiments, A²is cyclopropyl.

In certain embodiments, A¹ is selected from Cl, CN and cyclopropyl, andA² is selected from H, Cl and cyclopropyl.

In certain embodiments, A¹ is selected from CN, Cl and cyclopropyl, andA² is H.

In certain embodiments, A¹ is CN and A² is hydrogen.

In certain embodiments, A¹ is Cl and A² is hydrogen.

In certain embodiments, A¹ is cyclopropyl and A² is hydrogen.

In certain embodiments, A¹ is Cl and A² is Br.

In certain embodiments, A¹ and A² are both Cl.

In certain embodiments, A¹ is Cl and A² is cyclopropyl.

In certain embodiments, A¹ and A² are both cyclopropyl.

In certain embodiments, A¹ and A² are both hydrogen.

In certain embodiments, R^(7a) and R^(7b) are both hydrogen.

In certain embodiments, R^(7a) and R^(7b) are both methyl.

In certain embodiments, R^(7a) is hydrogen and R^(7b) is methyl.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ ismethyl.

In certain embodiments, each of R^(7a), R^(7b) and R⁸ is hydrogen.

In certain embodiments, R⁹ is hydrogen or fluoro.

In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ isfluoro.

In certain embodiments, R⁹ is methyl. In certain embodiments, R⁹ is NO₂.

In certain embodiments, R¹⁰ is hydrogen or fluoro.

In certain embodiments, R¹⁰ is hydrogen. In certain embodiments, R¹⁰ isfluoro. In certain embodiments, R¹⁰ is methyl.

In certain embodiments, each of R⁹ and R¹⁰ is hydrogen.

In certain embodiments, each of R^(7a), R^(7b), R⁸, R⁹ and R¹⁰ ishydrogen.

In one embodiment, W is —CONR¹—. An example of a particular value for R¹is hydrogen. In one embodiment, W is —NR²CO—. In one embodiment R² ishydrogen. In another embodiment, R² is methyl. Examples of values for Ware —C(═O)NH—, —NHC(═O)— and —N(CH₃)CO—.

In a particular embodiment, W is —C(═O)NH—.

In one embodiment, L is a bond.

In one embodiment, L is —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*.

In certain embodiments when L is—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, n is 0 or 1 and m is 0, 1 or2. In certain embodiments, each of R³, R⁴, R^(a), R^(b), R⁵ and R⁶ ishydrogen such that L is selected from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— and—CH₂CH₂CH₂CH₂—.

In certain embodiments when L is —(CR³,R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—* where one of m or n is 0.

In certain embodiments, L is a bond and CH₂CH₂.

In certain embodiments when L is—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, n is 0 or 1, m is 1 or 2, andR⁵ and R⁶ together with the atom to which they are attached form acyclopropyl ring. In certain embodiments, each of R³ and R⁴ when n is 1and each of R^(a) and R^(b) is hydrogen. Particular values for L include—CH₂(cycloprop-1,1-diyl) and —CH₂CH₂(cycloprop-1,1-diyl) groups havingthe structures:

In certain embodiments when L is—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, R⁵ is hydrogen, (1-4C alkyl),OH, —O(1-4C alkyl) or F, and R⁶ is hydrogen, F or methyl. In certainembodiments, n is 1 and m is 0. In certain embodiments, each of R³ andR⁴ is hydrogen. Particular values for L include the structures:

wherein the asterisk indicates the point of attachment to the G group.

In certain embodiments when L is—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, n is 1, m is 0, 1 or 2, R³ ishydrogen, (1-4C alkyl) or —CH₂OH, and R⁴ is hydrogen or methyl. Incertain embodiments, each of R^(a), R^(b), R⁵ and R⁶ is hydrogen. Incertain embodiments, m is 0 and each of R⁵ and R⁶ is hydrogen.Particular values for L include the structures:

wherein the asterisk indicates the point of attachment to the G group.

In certain embodiments, L is (2-4C)alkenylene. Particular values for Linclude —CH₂═CH₂— and —CH₂CH₂CH═CH₂—.

In certain embodiments, L is —O(1-4C alkyl)-* wherein the asteriskindicates the point of attachment to the G group. A particular value is—OCH₂—*.

In certain embodiments, L is -(1-4C alkyl)-O—* wherein the asteriskindicates the point of attachment to the G group. A particular value is—CH₂CH₂O—*.

In certain embodiments, L is -(1-4C alkyl)-S—* wherein the asteriskindicates the point of attachment to the G group. A particular value is—CH₂CH₂S—*.

In certain embodiments, L is (3-6C)cycloalkylene, that is, a divalentcycloalkyl ring having from 3-6 carbon atoms in the ring, wherein theradicals are located on different carbon atoms within the ring. Examplesinclude cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylenerings. Particular values for L include the structures:

In certain embodiments, L is hetCyc¹ which is represented the formula

where t and p are as defined herein and the asterisk indicates the pointof attachment to the G group. Particular values for L include thestructures:

In certain embodiments of Formula I, L is selected from a bond,—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, (3-6C)cycloalkylene, —O(1-4Calkyl)-*, -(1-4C alkyl)-O—*, and -(1-4C alkyl)-S—.

In certain embodiments of Formula I, L is selected from hetCyc¹, —O(1-4Calkyl)-*, -(1-4C alkyl)-O—*, and -(1-4C alkyl)-S—*.

In certain embodiments of Formula I, L is selected from —O(1-4Calkyl)-*, -(1-4C alkyl)-O—*, and -(1-4C alkyl)-S—*.

In certain embodiments of Formula I, L is hetCyc¹.

In certain embodiments of Formula I, L is selected from a bond,—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, and (3-6C)cycloalkylene.

In certain embodiments of Formula I, L is selected from a bond and—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*.

In certain embodiments of Formula I, L is selected from a bond andCH₂CH₂.

In certain embodiments, the G group is Ar¹.

In certain embodiments, Ar¹ is phenyl optionally substituted with one ormore substituents independently selected from F, Cl, Br, CF₃,(1-4C)alkyl, OH, —O(1-4C alkyl), —S(1-3C alkyl), —SCF₃, cyclopropyl,—CH₂N(1-3C alkyl)₂, —O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl—O-(1-3C)trifluoroalkyl, —OCH₂(cyclopropyl), and (3-4C)alkynyl.

In particular embodiments, Ar¹ is phenyl optionally substituted with oneor more substituents independently selected from F, Cl, Br, CF₃, methyl,ethyl, propyl, tert-butyl, OH, methoxy, ethoxy, propoxy, isopropoxy,tert-butoxy, SMe, SCF₃, cyclopropyl, CH₂NMe₂, OCH₂CH₂F, OCH₂CH₂CH₂F,OCHF₂, OCF₃, —OCH₂(cyclopropyl), and propynyl. In certain embodiments,Ar¹ is phenyl optionally substituted with 2 of said substituents. Incertain embodiments, Ar¹ is phenyl optionally substituted with 3 of saidsubstituents.

Particular values for G when represented by Ar¹ include phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2,3-dichloropyhenyl, 3,5-dichlorophenyl, 2-chloro-6-fluorophenyl,2-chloro-4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 2-bromophenyl, 4-bromophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2,4-dimethylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-tert-butoxyphenyl,2-ethoxyphenyl, 3-isopropoxyphenyl, 2-trifluoromethoxyphenyl,2-thiomethylphenyl, 3-thiomethylphenyl, 4-thiomethylphenyl,4-trifluoromethylthiophenyl, 2-cyclopropylphenyl, 4-cyclopropylphenyl,3-tert-butylphenyl, 4-tert-butylphenyl, 4-(dimethylamino)methylphenyl,3,4-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl,3-methoxy-4-chlorophenyl, 2-chloro-4-methoxyphenyl,2-methoxy-4-bromophenyl, 2-methoxy-4-chlorophenyl,2-methoxy-4-fluorophenyl, 2-methoxy-4-trifluoromethylphenyl,2-methoxy-4-cyclopropylphenyl, 2-fluoro-5-chlorophenyl,2-chloro-4-trifluoromethylphenyl, 2-chloro-4-bromophenyl,2-methyl-4-chlorophenyl, 2,5-dimethoxyphenyl, 2-methoxy-5-bromophenyl,2-bromo-4-chlorophenyl, 2-chloro-4-cyclopropylphenyl,2-cyclopropyl-4-chlorophenyl, 2,4-dichloro-6-methoxyphenyl,3-methoxy-4-chlorophenyl, 4-difluoromethoxyphenyl,2-chloro-4,6-dimethoxyphenyl, 2,6-dimethoxyphenyl,4-chloro-2,6-dimethoxyphenyl, 2-chloro-6-methoxyphenyl,2,4-dichloro-6-ethoxyphenyl, 2-methyl-4-chlorophenyl,2-ethyl-4-chlorophenyl, 2-propyl-4-chlorophenyl,2,6-dichloro-4-methoxyphenyl, 2-trifluoromethyl-4-chlorophenyl,2,4-diethoxyphenyl, 3,5-dimethoxyphenyl, 2-methoxy-3-chlorophenyl,3-chloro-5-methoxyphenyl, 2,4-trifluoromethylphenyl, 2-ethylphenyl,2-thiomethyl-4-chlorophenyl, 2-ethoxy-4-methoxyphenyl,2-methoxy-5-chlorophenyl, 2-ethoxy-4-chlorophenyl,2-trifluoromethoxy-4-chlorophenyl, 2-tert-butoxy-4-chlorophenyl,2-cyclopropylmethoxy-4-chlorophenyl, 2-isopropoxy-4-chlorophenyl,2-ethoxy-4-chlorophenyl, 2-propoxy-5-chlorophenyl,4-chloro-2-(2-fluoroethoxy)phenyl, 4-chloro-2-(3-fluoropropoxy)phenyl,and 2-chloro-4-(propyn-1-yl)phenyl.

Additional values for G when represented by Ar¹ include2,4-di(trifluoromethyl)phenyl, 2-cyclopropyl-4-trifluoromethylphenyl,2,4,6-trimethoxyphenyl, 2-methoxy-4-ethoxyphenyl,2-fluoro-4-chlorophenyl and 2-hydroxy-4-chlorophenyl.

In certain embodiments of Formula I, G is Ar².

In certain embodiments, Ar² is a phenyl group substituted with Ar³,wherein Ar² is optionally further substituted with one or moresubstituents independently selected from F, Cl and CF₃. Examples of Ar³include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, and2,3-dimethylphenyl.

Particular values for G when represented by Ar² include the structures:

In certain embodiments of Formula I, G is Ar² and Ar² is phenylsubstituted with O—Ar⁴, wherein the Ar² group is optionally furthersubstituted with one or more substituents independently selected from F,Cl and CF₃. Examples of O—Ar⁴ substituents include phenoxy groupsoptionally substituted with fluoro, chloro or bromo. Particular examplesof O—Ar⁴ can be represented by the structure:

where X¹ and X² are independently selected from fluoro, chloro andbromo.

Examples of G when represented by Ar² include the structures:

wherein X¹ and X² are independently selected from fluoro, chloro andbromo.

Particular examples of G when represented by Ar² include the structures:

In certain embodiments of Formula I, G is Ar² and Ar² is phenylsubstituted with hetAr¹, wherein said Ar² is optionally furthersubstituted with one or more substituents independently selected from F,Cl and CF₃. Examples of hetAr¹ substituents include pyridyl andpyrimidyl rings. In certain embodiments, hetAr¹ is substituted with oneor more (1-4C alkyl) groups, for example, one or more methyl groups.Particular examples of hetAr¹ include methylpyrimidyl groups, such as2-methylpyrimidyl. A particular example of G when represented by Ar² isthe structure:

In certain embodiments of Formula I, G is Ar² wherein Ar² is phenylsubstituted with —O-hetAr², wherein said Ar² is optionally furthersubstituted with one or more substituents independently selected from F,Cl and CF₃. Examples of O-hetAr² include pyridinyloxy and pyrimidinyloxygroups, each of which is optionally substituted with CF₃. Examples of Gwhen represented by Ar² include the structures:

Particular examples of G when represented by Ar² include the structures:

In certain embodiments, G is naphthyl. Examples include 1-naphthyl and2-naphthyl.

In certain embodiments, G is a benzo-fused (5-6C)cycloalkyl ringoptionally substituted with one or more substituents independentlyselected from Cl and OMe. Examples of benzo-fused (5-6C)cycloalkyl ringinclude unsubstituted and substituted 2,3-dihydro-1H-indenyl andtetrahydronaphthyl rings, for example unsubstituted and substituted2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl,1,2,3,4-tetrahydronaphth-2-yl rings. Particular values for the G groupinclude the structures:

In certain embodiments, G is a benzo-fused 5-6 membered heterocyclehaving 1-2 ring heteroatoms independently selected from O and N.Examples include chromanyl, tetrahydroquinolinyl, and benzodioxolylrings. Particular values for G include the structures:

In certain embodiments, G is a (3-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from(1-4C)alkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl rings optionally substituted with one or more alkyl groups,such as one or more methyl, ethyl, propyl, isopropyl, butyl and t-butylgroups. In certain embodiments G is a cycloalkyl group substituted withone or more methyl or t-butyl groups. Particular examples of G includethe structures:

In certain embodiments, G is an oxaspirononanyl ring. A particularexample is 1-oxaspiro[4.4]nonanyl.

In certain embodiments, G is a tert-butyl group.

In certain embodiments, G is selected from Ar¹, Ar² and a(3-6C)cycloalkyl ring.

In certain embodiments, G is selected from Ar¹ and Ar².

In certain embodiments, G is selected from Ar¹ and Ar², where Ar² isphenyl substituted with Ar³.

Particular embodiments of Formula I include compounds wherein:

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br, CF₃, methyl, ethyl, propyl,tert-butyl, OH, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, SMe,SCF₃, cyclopropyl, CH₂NMe₂, OCH₂CH₂F, OCH₂CH₂CH₂F, OCHF₂, OCF₃,—OCH₂(cyclopropyl), and propynyl;

Ar³ is selected from phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, and2,3-dimethylphenyl;

—O—Ar⁴ is selected from groups having the formula

where X¹ and X² are independently selected from fluoro, chloro andbromo;

hetAr¹ is selected from a pyridyl and pyrimidyl ring, each of which isoptionally substituted with one or more (1-4C alkyl) groups; and

O-hetAr² is selected from pyridinyloxy and pyrimidinyloxy groups, eachof which is optionally substituted with CF₃.

Examples of particular values for -L-G- groups include groups wherein:

L is a bond and G is Ar¹, Ar², naphthyl, a benzo-fused (5-6 C)cycloalkylring, a benzofused-5-6 membered heterocyclic ring, a (3-6C)cycloalkylring, or an oxaspirononanyl ring;

L is CH₂ and G is Ar¹, naphthyl, or a benzo-fused (5-6 C)cycloalkylring;

L is CH₂CH₂ and G is Ar¹, Ar², naphthyl, (3-6C cycloalkyl), ortert-butyl;

L is —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— and G is Ar¹;

L is CH₂CH₂CH═CH and G is Ar¹;

L is —OCH₂ and G is Ar¹;

L is CH₂CH₂S— and G is Ar¹;

L is CH₂CH₂O— and G is Ar¹;

L is hetCyc¹ and G is Ar¹; and

L is (3-6C)cycloalkylene and G is Ar¹;

wherein each of the above G groups is optionally substituted as definedherein.

In certain embodiments of Formula I, -L-G- is a group wherein L is abond or CH₂CH₂ and G is Ar¹, Ar², naphthyl, (3-6C cycloalkyl), ortert-butyl, or a group wherein L is—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— where one of m or n is 0 and Gis Ar¹.

In particular embodiments of Formula I, -L-G- is a group wherein L is abond or CH₂CH₂ and G is Ar¹, Ar² or a (3-6C)cycloalkyl ring, or a groupwherein L is —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— and G is Ar¹.

In certain embodiments of Formula I, -L-G- is a group wherein L is abond or CH₂CH₂ and G is Ar¹ or Ar², or a group wherein L is—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— and G is Ar¹.

In certain embodiments of Formula I, -L-G- is a group wherein L is abond or —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— and G is Ar¹.

In each of the above-described -L-G- combinations, G is optionallysubstituted as described for Formula I.

In certain embodiments of the -L-G- combinations above, W is C(═O)NH.

Compounds of Formula I include compounds of Formula Ia wherein:

A¹ is CN, Cl, or cyclopropyl;

A² is hydrogen, Cl, Br, or cyclopropyl;

W is —C(═O)NH—;

L is as defined for Formula I;

G is Ar¹, Ar², naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from Cland OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2heteroatoms independently selected from O and N, or a (3-6C)cycloalkylring optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl;

Ar¹ is as defined for Formula I;

Ar² is as defined for Formula I;

R^(7a), R^(7b) and R⁸ are each independently hydrogen;

R⁹ is hydrogen, methyl, fluoro or NO₂; and

R¹⁰ is hydrogen, methyl or fluoro.

Compounds of Formula I also include compounds of Formula Ib wherein:

A¹ is CN, Cl, or cyclopropyl;

A² is hydrogen, Cl, Br, or cyclopropyl;

W is —C(═O)NH—;

L is as defined for Formula I;

G is Ar¹, Ar², naphthyl, or a (3-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from(1-4C)alkyl;

Ar¹ is as defined for Formula I;

Ar² is as defined for Formula I;

R^(7a), R^(7b) and R⁸ are each independently hydrogen;

R⁹ is hydrogen, methyl, fluoro or NO₂; and

R¹⁰ is hydrogen, methyl or fluoro.

Compounds of Formula I also include compounds of Formula Ic wherein:

A¹ is CN, Cl, or cyclopropyl;

A² is hydrogen, Cl, Br, or cyclopropyl;

W is —C(═O)NH—;

L is a bond or —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— wherein R³, R⁴,R^(a), R^(b), R⁵ and R⁶ are as defined for Formula I;

G is Ar¹, Ar², naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from Cland OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2heteroatoms independently selected from O and N, or a (3-6C)cycloalkylring optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl;

Ar¹ is as defined for Formula I;

Ar² is as defined for Formula I;

R^(7a), R^(7b) and R⁸ are each independently hydrogen;

R⁹ is hydrogen, methyl, fluoro or NO₂; and

R¹⁰ is hydrogen, methyl or fluoro.

In a particular embodiment of Formula Ic, L is a bond or CH₂CH₂.

Compounds of Formula I also include compounds of Formula Id wherein:

A¹ is CN, Cl, or cyclopropyl;

A² is hydrogen, Cl, Br, or cyclopropyl;

W is —C(═O)NH—;

L is a bond or —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)— wherein R³, R⁴,R^(a), R^(b), R⁵ and R⁶ are as defined for Formula I;

G is Ar¹, Ar², naphthyl or a (3-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from(1-4C)alkyl;

Ar¹ is as defined for Formula I;

Ar² is as defined for Formula I;

R^(7a), R^(7b) and R⁸ are each independently hydrogen;

R⁹ is hydrogen, methyl, fluoro; and

R¹⁰ is hydrogen, methyl or fluoro.

In a particular embodiment of Formula Id, L is a bond or CH₂CH₂.

In certain embodiments of Formula Id, G is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more substituents independentlyselected from F, Cl, Br, CF₃, methyl, ethyl, propyl, tert-butyl, OH,methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, SMe, SCF₃,cyclopropyl, CH₂NMe₂, OCH₂CH₂F, OCH₂CH₂CH₂F, OCHF₂, OCF₃,—OCH₂(cyclopropyl), and propynyl. In certain embodiments, Ar¹ issubstituted with one to three of said substituents. In certainembodiments, Ar¹ is substituted with two of said substituents.

According to another aspect, the present invention provides a processfor the preparation of a compound of Formula I or a salt thereof asdefined hereinabove, which comprises:

(a) for a compound of Formula I in which A¹ is CN and A² is hydrogen,reacting a corresponding compound having the formula (II):

in which P¹ represents a hydrogen atom or a carboxyl protecting groupand Z¹ represents a leaving atom or group, with a corresponding compoundhaving the formula (III)

in the presence of a base; or

(b) coupling a compound of formula (IV)

in which P² is as defined for P¹ and Z² represents —NH₂ or —C(═O)OH, ora reactive derivative thereof, with a compound of formula (V)

H—Z³-L-G  (V)

in which Z³ represents OC(═O) or NH, respectively, or a reactivederivative thereof; or

(c) for a compound of Formula I in which A¹ is Cl, (1-4C alkyl), OMe orcyclopropyl and A² is (1-4C alkyl), chloro, bromo or cyclopropyl,coupling a compound having the formula (VI)

in which P³ is as defined for P¹ and A¹ is Cl, (1-4C alkyl), orcyclopropyl, and A² is (1-4C alkyl), chloro, bromo or cyclopropyl, witha corresponding compound having the formula (VII)

wherein E is an electron withdrawing group and Z⁴ is a leaving atom, inthe presence of a base, and if desired removing said electronwithdrawing group; or

(d) for a compound of Formula I where G is Ar^(x) where Ar^(x) is (1)Ar¹ substituted with cyclopropyl or (1-4C)alkyl and optionally furthersubstituted as defined for Ar¹, or (2) Ar² where Ar² is phenylsubstituted with Ar³ and optionally further substituted with F or Cl,reacting a corresponding compound having the formula (VIII)

where P⁴ is as defined for P¹ and Z⁵ is a leaving atom or group, with acompound having the formula Y—B(OH)₂ where Y is cyclopropyl, (1-4Calkyl) or Ar³, in the presence of a transition metal catalyst and aligand; or

(e) for a compound of Formula I where L is a bond and G is Ar¹ or Ar²,reacting a corresponding compound having the formula (IX)

wherein P⁵ is as defined for P¹, with a compound having the formulaAr¹—Z⁶ or Ar²—Z⁶ where Z⁶ is a leaving atom or group, in the presence ofa metal catalyst and a ligand; or

(f) for a compound of Formula I where A¹ is chloro, A² is cyclopropyl,R⁹ and R¹⁰ are hydrogen, and W is C(═O)NH, reacting a correspondingcompound having the formula (X)

wherein P⁶ is as defined for P¹, E is an electron withdrawing group, andB is O-tertbutyl, NH₂ or NH-L-G, with about 2 equivalents ofcyclopropylboronic acid in the presence of a suitable base, a metalcatalyst and a ligand at temperatures between about 100° C. and about150° C., followed by removal of the electron withdrawing group, ifdesired, and coupling with a compound having the formula H₂N-L-G when Bis O-tBu or coupling with a compound having the formula X-L-G when B isNH₂, where X is a leaving group or atom; or

(g) for a compound of Formula I where A¹ is cyclopropyl, A² iscyclopropyl, R⁹ and R¹⁰ are hydrogen and W is C(═O)NH, reacting acorresponding compound having the formula (X) with about 4 equivalentsof cyclopropylboronic acid in the presence of a suitable base, a metalcatalyst and a ligand at temperatures between about 100° C. and 150° C.,followed by removal of the electron withdrawing group, if desired, andcoupling with a compound having the formula H₂N-L-G when B is O-tBu orcoupling with a compound having the formula X-L-G when B is NH₂, where Xis a leaving group or atom; or

(h) for a compound of Formula I where A¹ is cyclopropyl, A² is hydrogen,R⁹ and R¹⁰ are hydrogen and W is C(═O)NH, reacting a correspondingcompound having the formula (XI)

with about 3 equivalents of cyclopropylboronic acid in the presence of asuitable base, a metal catalyst and a ligand at temperatures betweenabout 90° C. and 150° C., for example 120° C., followed by removal ofthe electron withdrawing group, if desired, and coupling with a compoundhaving the formula H₂N-L-G when B is O-tBu or coupling with a compoundhaving the formula X-L-G when B is NH₂, where X is a leaving group oratom; and

removing any protecting group or groups and, if desired, forming a salt.

The carboxyl protecting groups in any of the above methods may be anyconvenient carboxyl protecting group, for example as described in Greene& Wuts, eds., “Protecting Groups in Organic Synthesis”, John Wiley &Sons, Inc. Examples of carboxyl protecting groups include (1-6C)alkylgroups, such as methyl, ethyl and t-butyl. Removal of the carboxylprotecting group may be performed using methods known in the art. Forexample, alkyl protecting groups can be removed by hydrolysis, forexample, by treating the protected compound with a metal hydroxide, forexample lithium, potassium or sodium hydroxide, in a suitable solventsuch as THF or an alcohol (for example ethanol) or mixtures thereof.Tert-butyl protecting groups can be removed by acid hydrolysis, forexample with TFA or hydrogen chloride in an organic solvent.

Referring to process (a), the leaving atom represented by Z¹ may be, forexample, a halogen atom such as a fluorine atom. Alternatively, Z¹ maybe a leaving group such as a triflate or tosylate. The base may be, forexample, an alkali metal hydride or carbonate, such as sodium hydride,sodium carbonate or potassium carbonate, or a tertiary amine, such astriethylamine, or N,N-diisopropylethylamine. Convenient solvents includeN-methylpyrrolidinone, or amides, sulfoxides and nitriles, such as DMF,DMSO or acetonitrile. The reaction can be performed at an elevatedtemperature, such as in the range of from 50 to 150° C.

Compounds of formula (II) are known or can be prepared by treating thecorresponding bromo derivative having formula (IIa)

with Cu(I)CN in an appropriate solvent, such as N-methylpyrrolidone. Thereaction is conveniently performed at elevated temperatures, for examplebetween 100 and 200° C., such as at 160° C.

Compounds of formula (IIa) can be prepared by treating the correspondingderivative having formula (IIb)

with N-bromosuccinimide in an appropriate solvent, such as DMF. Thereaction is conveniently performed at temperatures between ambienttemperature and 100° C., for example at 50° C.

Compounds of formula (IIb) wherein R⁸ is Me can be prepared by reactinga corresponding compound of formula (IIb) wherein R⁸ is H with methyliodide in the presence of a suitable base, such as an alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate or cesiumcarbonate) or an alkali metal hydride (e.g., sodium hydride).

Compounds of formula (IIb) can be prepared by homologating acorresponding compound having formula (IIc)

using methodologies known in the art [such as via enol ethers, epoxides,cyanohydrins, α,β-unsaturated sulfones, ketene thioacetals, glycidicesters, nitriles and α-acetoxyacrylonitriles], to add the one carbonunit followed by reductive hydrolysis with tin(II) chloride under acidicconditions. For example, in one embodiment, the compound of formula(IIc) can be treated with trimethylsilylnitrile and a catalyst such aszinc iodide or I₂, either neat or in a suitable solvent, for exampledichloromethane. The reaction is conveniently performed at ambienttemperature.

Compound of formula (IIb) wherein R^(7a) and R^(7b) are each Me can beprepared by cyclizing a compound having the formula

with 2-propanone in the presence of a suitable base, for example anamine base such as pyrrolidine. The reaction is conveniently preformedat elevated temperatures, such as between 50-100° C., for example 80° C.

Referring to process (b), the coupling of the compound of formula (IV)with a compound of formula (V) may be performed using conventional amidebond formation conditions, for example by treating the carboxylic acidwith an activating agent, followed by addition of the amine in thepresence of a base. Suitable activating agents include oxalyl chloride,thionyl chloride, EDCI, HATU, and HOBt. Suitable bases include aminebases, for example triethylamine, diisopropylethylamine, pyridine, orexcess ammonia. Suitable solvents include DCM, DCE, THF, and DMF.

Alternatively, the amide bond formation can be performed by coupling areactive derivative of a carboxylic acid, for example an acid halide,such as an acid chloride.

In a particular embodiment, a compound of formula (IV) where A¹ is Cl,A² is hydrogen and Z² is CO₂H can be prepared by coupling a compoundhaving the formula (IVa)

with a corresponding compound having the formula

where Z⁷ is a leaving atom or group, in the presence of copper(I)chloride and an inorganic base, followed by hydrolysis of the ester toform the corresponding acid. Suitable inorganic bases includecarbonates, such as cesium carbonate. Leaving atoms represented by Z⁷include halogen atoms, for example Br or I. Alternatively, Z⁷ can be aleaving group such as an alkylsulfonyl or arylsulfonyl group, forexample, a triflate group.

Referring to process (c), examples of leaving atoms represented by Z⁴include halogen atoms, for example F and Cl. Alternatively, Z⁵ can be aleaving group such as an alkylsulfonyl or arylsulfonyl group, forexample, a triflate group. Examples of electron withdrawing groupsinclude NO₂. In embodiments wherein the electron withdrawing group isNO₂, this group can be removed, if desired, by reducing the nitro groupto an amino group using any convenient reducing conditions (for example,Zn and NH₄Cl) followed by cleavage of the amino group (for example, bytreating the amino compound with isobutyl nitrite).

Referring to process (d), examples of a leaving atom represented by Z⁵include F, Cl, Br and I. Alternatively, Z⁵ can be a leaving group suchas an alkylsulfonyl or arylsulfonyl group, for example, a triflategroup. Suitable transition metal catalysts include palladium catalysts,such as Pd(II) catalysts, for example Pd(OAc)₂ in the presence of asuitable ligand. The ligand can be a phosphine ligand, such as PPh₃.Suitable bases include inorganic bases, for example alkali metalcarbonates such as potassium carbonate, sodium carbonate or cesiumcarbonate. The reaction is conveniently performed in a suitable solventsuch as DMF, DMA, DMSO, NMP or dioxane, at temperatures ranging fromabout 50-160° C.

Referring to method (e), the leaving atom represented by Z⁶ can be ahalogen atom, for example F, Cl, Br, or I. Alternatively, Z⁵ can be aleaving group such as an alkylsulfonyl or arylsulfonyl group, forexample, a triflate group. Suitable metal catalysts include palladiumcatalysts, such as Pd(II) catalysts, for example Pd(OAc)₂ in thepresence of a suitable ligand. The ligand can be a phosphine ligand,such as PPh₃. The reaction is conveniently performed in the presence ofan inorganic base such as an alkali metal carbonate (for example sodiumcarbonate or cesium carbonate) in a suitable solvent, such as toluene,DMF, THF, or NMP. The reaction is conveniently performed at temperaturesranging from 50-160° C.

Referring to processes (f), (g) and (h), suitable bases includeinorganic bases, for example alkali metal phosphates, such as potassiumphosphate. Suitable catalysts include palladium catalysts, such asPd(II) catalysts, for example Pd(OAc)₂ in the presence of a suitableligand. The ligand can be a phosphine ligand, such astricyclohexylphosphine. Examples of electron withdrawing groups includeNO₂. In embodiments wherein the electron withdrawing group is NO₂, thisgroup can be removed, if desired, by reducing the nitro group to anamino group using any convenient reducing conditions (for example, Znand NH₄Cl) followed by cleavage of the amino group (for example, bytreating the amino compound with isobutyl nitrite). Suitable solventsinclude xylene and toluene. The reaction is conveniently performed atthe reflux temperature of the solvent.

The compounds of Formulas (IV), (VI), (VIII), (IX, (X) and (XI) are alsobelieved to be novel and are provided as further aspects of thisinvention.

Also provided herein is a compound of general Formula Ie:

or a salt thereof, wherein:

Pg is a carboxyl protecting group;

A¹ is hydrogen, CN, Cl, F, Br, OMe, (1-4C alkyl) or cyclopropyl;

A² is hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl;

W is —C(═O)NR¹— or —NR²C(═O)—;

R¹ and R² are each hydrogen or methyl;

L is a bond, —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, (2-4C)alkenylene,—O(1-4C alkyl)-*, -(1-4C alkyl)-O—*, -(1-4C alkyl)-S—*,(3-6C)cycloalkylene, or hetCyc¹, wherein the * indicates the point ofattachment to G, provided that when W is —NR²C(═O)— then L is not—(CH═CH)—;

m=0, 1 or 2;

n=0 or 1;

R^(a) and R^(b) are independently selected from hydrogen and (1-4Calkyl);

R³ is hydrogen, (1-4C alkyl) or CH₂OH;

R⁴ is hydrogen or methyl;

R⁵ is hydrogen, (1-4C alkyl), OH, —O(1-4C alkyl) or F;

R⁶ is hydrogen, F or methyl,

or R⁵ and R⁶ together with the carbon to which they are attached form acyclopropyl ring;

hetCyc¹ is a group having the formula

where t is 1 or 2 and p is 0 or 1, and the * indicates the point ofattachment to G;

G is Ar¹, Ar², naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionallysubstituted with one or more substituents independently selected from Cland OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2heteroatoms independently selected from O and N, a (3-6C)cycloalkyl ringoptionally substituted with one or more substituents independentlyselected from (1-4C)alkyl, an oxaspirononanyl ring, or t-butyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br, CF₃, (1-4C)alkyl, OH, —O(1-4Calkyl), —S(1-3C alkyl), —SCF₃, cyclopropyl, —CH₂N(1-3C alkyl)₂,—O-(2-3C)fluoroalkyl, —O-(1-3C)difluoro alkyl —O-(1-3C)trifluoro alkyl,—OCH₂(cyclopropyl), and (3-4C)alkynyl;

Ar² is phenyl which is substituted with Ar³, —O—Ar⁴, hetAr¹ or—O-hetAr², wherein Ar² is optionally further substituted with one ormore substituents independently selected from F, Cl and CF₃;

Ar³ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br and (1-4C alkyl);

Ar⁴ is phenyl optionally substituted with one or more substituentsindependently selected from F, Cl, Br and (1-4C alkyl);

hetAr¹ is a 6-membered heteroaryl having 1-2 nitrogen atoms andoptionally substituted with one or more substituents independentlyselected from (1-4C alkyl);

hetAr² is a 6-membered heteroaryl having 1-2 nitrogen atoms andoptionally substituted with one or more substituents independentlyselected from (1-4C alkyl) and CF₃;

R^(7a), R^(7b) and R⁸ are each independently hydrogen or methyl;

R⁹ is hydrogen, methyl, fluoro or NO₂; and

R¹⁰ is hydrogen, methyl or fluoro.

The protecting group represented by Pg in Formula Ie may be anyconvenient carboxyl protecting group, for example as described in Greene& Wuts, eds., “Protecting Groups in Organic Synthesis”, John Wiley &Sons, Inc. Examples of carboxyl protecting groups include (1-6C)alkylgroups, such as methyl, ethyl and t-butyl.

It will be appreciated that the afformentioned processes can comprisethe formation of an intermediate of Formula Ie in which Pg is a carboxylprotecting group (for example (1-6C)alkyl, such as methyl or ethyl),which protecting group is removed to afford a compound of Formula I.Such compounds form a further aspect of the invention. Compounds ofFormula Ie may also function as prodrugs of compounds of Formula I.

The ability of test compounds to act as DP2 receptor antagonists may bedemonstrated by the assay described in Example A.

Compounds which are antagonists of DP2 are useful in the treatment ofdiseases or disorders mediated by PGD₂, for example, diseases ordisorders associated with overproduction or dysregulation of PGD₂.

As used herein, the term treatment includes prophylaxis as well astreatment of an existing condition.

Examples of disorders or diseases that may be treated with compoundsaccording to the invention include immunologic diseases. In addition,compounds of the invention may be useful for treating inflammatorydiseases and disorders. Compounds of the invention may also be usefulfor treating itching/pruritis.

Examples of immunologic diseases include allergic inflammatory diseasesuch as asthma, dermatitis, allergic rhinitis, urticaria, anaphylaxis,angioedemea, allergies, contact hypersensitivity (e.g., nickelsensitivity), drug hypersensitivity, and allergic conjunctivitis inaddition to inflammatory autoimmune diseases such as hyper-eosinophilicsyndromes, psoriasis, systemic mast cell disorders, chronic obstructivepulmonary disease, inflammatory bowel disease, and arthritis.

Examples of immunologic diseases include allergic inflammatory diseases,such as asthma, atopic dermatitis, allergic rhinitis, seasonalallergies, food allergies, contact hypersensitivity (e.g., nickelsensitivity), hyper-eosinophilic syndromes, and allergic conjunctivitis.

Further examples of allergic inflammatory diseases include asthma(including mild-to-moderate asthma, severe asthma, refractory asthma,steroid-resistant asthma, steroid-insensitive asthma, andexercise-induced asthma), allergies such as severe allergy/anaphylaxis,food allergies, plant allergies, drug allergies, latex allergy, allergicreactions to venemous stings, seasonal allergic rhinitis, and perrennialallergic rhinitis, chronic rhinosinusitis, cystic fibrosis, eosinophilicdiseases and disorders (including eosinophilic gastroenteritis,eosinophilic esophagitis, acute eosinophilic pneumonia, chroniceosinophilic pneumonia, pulmonary eosinophilia (Loeffler's Disease),eosinophilia-myalgia syndrome, Chrug-Strauss syndrome, eosinophilicfasciitis, familial eosinophilic cellulitis, cutaneous eosinophilia,nonallergic rhinitis with eosinophilia syndrome, familial eosinophilia,and drug reaction with eosinophilia and systemic symptoms), hyper IgEsyndrome, allergic diseases of the gastrointestinal tract, celiac sprue,gluten enteropathy, gluten intolerance, acute hypersensitivy reaction,and delayed hypersensitivity reaction.

Further examples of allergic inflammatory diseases include severeallergy/anaphylaxis, eosinophilic gastroenteritis, eosinophilicesophagitis, severe asthma, refractory asthma, steroid-resistanceasthma, allergic diseases of the gastrointestinal tract, celiac sprue,gluten enteropathy, gluten intolerance, acute hypersensitivy reaction,and delayed hypersensitivity reaction.

Additional diseases or disorders which may be treated with compounds ofthis invention include inflammatory bowel diseases such as Crohn'sdisease, ulcerative colitis, ileitis and enteritis, vasculitis, Behcet'ssyndrome, psoriasis and inflammatory dermatoses such as dermatitis,eczema, urticaria, viral cutaneous pathologies such as those derivedfrom human papillomavirus, HIV or RLV infection, bacterial, fungal andother parasital cutaneous pathologies, and cutaneous lupuserythematosus, respiratory allergic diseases such as persensitivity lungdiseases, chronic obstructive pulmonary disease and the like, autoimmunediseases, such as arthritis (including rheumatoid and psoriatic),systemic lupus erythematosus, type I diabetes, myasthenia gravis,multiple sclerosis, Graves' disease, glomerulonephritis and the like,graft rejection (including allograft rejection and graft-v-hostdisease), e.g., skin graft rejection, solid organ transplant rejection,bone marrow transplant rejection, fever, cardiovascular disorders suchas acute heart failure, hypotension, hypertension, angina pectoris,myocardial infarction, cardiomyopathy, congestive heart failure,atherosclerosis, coronary artery disease, restenosis, thrombosis andvascular stenosis, cerebrovascular disorders such as traumatic braininjury, stroke, ischemic reperfusion injury and aneurysm, cancers of thebreast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung,liver, larynx, oral cavity, colon and gastrointestinal tract (e.g.,esophagus, stomach, pancreas), brain, thyroid, blood and lymphaticsystem, fibrosis, connective tissue disease and sarcoidosis, genital andreproductive conditions such as erectile dysfunction, gastrointestinaldisorders such as gastritis, ulcers, nausea, pancreatitis and vomiting;neurological disorders, such as Alzheimer's disease, sleep disorderssuch as insomnia, narcolepsy, sleep apnea syndrome and PickwickSyndrome, pain, renal disorders, ocular disorders such as glaucoma,infectious diseases, viral infections such as HIV, and bacterialinfections such as sepsis, inflammation, flushing, nasal congestion, andotitis media.

Additional diseases or disorders which may be treated with compounds ofthis invention include inflammatory bowel diseases such as IgAdeficiency, inflammatory dermatoses such as chronic urticaria, acuteurticaria, seborrheic dermatitis, contact dermatitis, pemphigus, andexfoliative dermatitis (etythroderma), dermatitis herpetiformis,trichinosis, visceral larva migraines, trichuriasis, ascariasis,strongyloidiasis, hookworm infection, clonorchiasis, pragonimiasis,fascioliasis, cysticerosis, echinococcosis, filariasis, schistocomiasis,brucellosis, cat scratch fever, infectious lymphocytosis, acutecoccidiodomycosis, infectious mononucleosis, mycobacterial disease,scarlet fever, tuberculosis, and cutaneous lupus erythematosus,respiratory allergic diseases such as hypersensitivity lung diseases,allergic broncopulmonary aspergillosis, tropical pulmonary eosinophilia,and the like, autoimmune diseases such as mastocytosis, leukocytoclasticvasculitis, urticarial vasculitis, basophilic leukocytosis, adrenalhypofunction and the like, cardiovascular disorders such asCoombs'-positive hemolytic anemias, Hashimoto's thyroiditis,Goodpasture's syndrome, serum sickness, polyarteritis nodosa, Dressler'ssyndrome, Wiskott-Aldrich syndrome, scleroderma, cirrhosis, andsarcoidosis, and ocular disorders such as vernal keratoconjunctivitis,atopic keartoconjunctivitis, giant papullary conjunctvitis.

Accordingly, another aspect of this invention provides a method oftreating diseases or medical conditions in a mammal mediated by PGD2,comprising administering to said mammal one or more compounds of FormulaI or a pharmaceutically acceptable salt or prodrug thereof in an amounteffective to treat or prevent said disorder.

Another aspect of this invention provides a method of treating diseasesor medical conditions in a mammal mediated by the DP2 receptorcomprising administering to said mammal one or more compounds of FormulaI or a pharmaceutically acceptable salt or prodrug thereof in an amounteffective to treat or prevent said disorder.

Another aspect of this invention provides a method of treating diseasesor medical conditions in a mammal involving the Th2 T cell viaproduction of IL-4, IL-5 and/or IL-13 comprising administering to saidmammal one or more compounds of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof in an amount effective to treat orprevent said disorder.

Another aspect of this invention provides a method of treating diseasesor medical conditions in a mammal involving the activation andtrafficking of granulocytes (mast cell, eosinophil, neutrophil,basophil, etc.) comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt or prodrugthereof in an amount effective to treat or prevent said disorder.

The phrase “effective amount” means an amount of compound that, whenadministered to a mammal in need of such treatment, is sufficient to (i)treat or prevent a particular disease, condition, or disorder mediatedby PGD2, (ii) attenuate, ameliorate, or eliminate one or more symptomsof the particular disease, condition, or disorder, or (iii) prevent ordelay the onset of one or more symptoms of the particular disease,condition, or disorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

This invention also provides compounds of Formula I for use in thetreatment of PGD2-mediated conditions.

An additional aspect of the invention is the use of a compound ofFormula I in the preparation of a medicament for therapy, such as forthe treatment or prevention PGD2-mediated conditions. Further, compoundswhich are antagonists of DP2 are useful in the treatment of diseases anddisorders mediated by metabolites of PGD2 and other prostaglandins (andtheir corresponding metabolites) that may be acting via the DP2receptor.

Compounds of the present invention can be used in combination with oneor more additional drugs that work by the same or a different mechanismof action. Examples include anti-inflammatory compounds, steroids (e.g.,dexamethasone, cortisone and fluticasone), NSAIDs (e.g., ibuprofen,indomethacin, and ketoprofen), anti-histamines, and anti-leukotrienes(e.g., Singulair®).

Compounds of the invention may be administered by any convenient route,e.g., by dermal application (i.e., topical application to the skin),transdermally, or into the gastrointestinal tract (e.g. rectally ororally), nose, lungs, musculature or vasculature.

Compounds may be administered in any convenient administrative form,e.g., creams, tablets, powders, capsules, solutions, dispersions,suspensions, syrups, sprays, suppositories, gels, emulsions, and drugdelivery devices such as patches, etc. Such compositions may containcomponents conventional in pharmaceutical preparations, e.g. diluents,carriers, pH modifiers, sweeteners, bulking agents, and further activeagents. If parenteral administration is desired, the compositions willbe sterile and in a solution or suspension form suitable for injectionor infusion. Such compositions form a further aspect of the invention.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove. In oneembodiment, the pharmaceutical composition includes the compound ofFormula I together with a pharmaceutically acceptable diluent orcarrier.

According to another aspect, the present invention provides a compoundof formula (I) or a pharmaceutically acceptable salt thereof, for use intreating an immunologic disorder.

According to a further aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament to treat an immunologic disorder, asdefined hereinabove.

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF), dichloromethane (CH₂Cl₂, methylene chloride),toluene, and dioxane were purchased from Aldrich in Sure seal bottlesand used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

¹HNMR spectra were obtained as CDCl₃ or CD₃OD solutions (reported inppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃:7.25 ppm; CD₃OD: 3.31 ppm) as the reference standard. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

Separation of racemic mixtures to isolate enantiomers was performed asdescribed below on a CHIRALCEL® OJ-H column (Chiral Technologies, WestChester, Pa.), in which the packing composition is cellulosetris(4-methylbenzoate) coated on 5 μM silica gel. Enantiomeric puritywas determined using a CHIRALPAK® QD-AX column ((Chiral Technologies,West Chester, Pa.), which is a quinidine (QD) based column.

Particular compounds of the invention include:

-   6-Cyano-7-(4-(4-chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-chlorophenylcarbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylic    acid;-   7-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylic    acid;-   6-Cyano-7-(4-(2,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;-   6-Cyano-7-(4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-Chlorobenzyloxycarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   6-Cyano-7-(4-(3,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-nitrophenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-phenylbutylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(3-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(4-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   (Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   (Z)-6-chloro-7-(4-(4-(2,4-dichlorophenyl)but-3-enylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-(2,4-dichlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-dimethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-cyclopropylethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2′,3-dichlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-chloro-4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(3-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2′,5-dichlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   8-bromo-6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6,8-dicyclopropylchroman-4-carboxylic    acid;-   6,8-dicyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6-cyclopropylchroman-4-carboxylic    acid;-   6-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-8-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-Cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid-   6-Cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-((2-Phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic    acid;-   7-(4-((3-Methoxyphenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic    acid;-   7-(4-((4-Fluorophenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic    acid;-   7-(4-((4-(Trifluoromethyl)phenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic    acid;-   7-(4-((2-(4-Chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic    acid;-   7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid-   6-Cyano-7-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(naphthalen-1-ylmethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-tert-Butylphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(2-Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(Biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(Biphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(4′-Chlorobiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   6-Cyano-7-(4-(3-(2-methylpyrimidin-4-yl)phenylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-Chloro-7-(4-(4′-chloro-6-fluorobiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(5-Chloro-2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   6-Cyano-7-(4-(4-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(naphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-difluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-chloro-6-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,5-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,3-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(5-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(4′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(3′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-chloro-4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-chloro-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-chloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-fluoro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(5-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(4′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(3′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-(p-tolylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(4-chlorophenylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2-chlorophenoxy)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(2-tert-butoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(1-(3-chlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)azetidin-3-ylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(1-(2,4-dichlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-((S)-1-(3-chlorophenyl)piperidin-3-ylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-Cyano-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   7-(4-(4-tert-Butylcyclohexylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(4-Chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;-   7-(4-(4-Chlorophenethylcarbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylic    acid;-   6-Cyano-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(1-(4-Chlorophenyl)propan-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(4-Chloro-3-methoxyphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   7-(4-(3-tert-Butylphenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   6-Cyano-7-(4-(3-isopropoxyphenylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,3-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-tert-butylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Cis-6-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Trans-6-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-Chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-(3-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-(4-methylphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-(4-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-(4-(methylthio)phenyl)cyclohexylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-Chloro-7-(4-(3-(3-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-phenylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-p-tolylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(3-(3-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(4-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(3-methylphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(3-(trifluoromethyl)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(3-fluorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(3-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(3-(3,4-dichlorophenyl)cyclopentylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(3-(4-methoxyphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-(4-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(3,3-dimethylbutylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-cyclohexylethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-3-methylphenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-(2-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-cyclopentylethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(1-oxaspiro[4.4]nonan-3-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3,5-dimethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(3-chloro-2-methoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(trifluoro-methyl)phenethyl-carbamoyl)phenoxy)    chroman-4-carboxylic acid;-   7-(4-(2-(benzo[d][1,3]dioxol-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(4-chlorophenyl)-2,2-difluoroethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-ethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-chloro-2-ethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(cyclopropyl-methoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(2-methoxyethoxy)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4,5-dichloro-2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-isopropoxy-phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(3,5-dichlorophen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)methylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-(4-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-phenoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(4-chlorophenoxy)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-(3-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(3-chlorophenoxy)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-(3,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-(2,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(2-fluoroethoxy)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(4-chloro-2-(3-fluoropropoxy)phenethylcarbamoyl)phenoxy)    chroman-4-carboxylic acid;-   6-chloro-7-(4-(2-chloro-6-methoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,6-dimethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   5-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-((1-(4-chlorophenyl)cyclopropyl)methylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-phenoxyethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   7-(4-(2,4-bis(trifluoromethyl)phenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4,6-trimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-(difluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,6-dichloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2,4-diethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-chloro-4,6-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-ethoxy-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-ethoxy-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(4-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-((5-chloro-2,3-dihydro-1H-inden-1-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-cyclopropyl-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-Chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylic    acid;-   Enantiomer 2 of    6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic    acid;

and salts thereof. Particular mention is made of the sodium salt of theaforementioned compounds.

EXAMPLE A DP-2 Binding Inhibition Assay

The coding sequence of human DP2 was introduced into the human Leukemiccell line K562 by electroporation and stable clones expressing DP2 wereobtained by limiting dilution followed by cell surface staining with arat monoclonal antibody specific for human DP2. Membranes were preparedfrom one of these DP2 expressing clones and used to determine theability of compounds of the present invention to inhibit binding ofprostaglandin D2 (PGD2) to its receptor DP2 in the presence of one ormore of the following serum protein concentrations, 0.1% BSA, 1% HSA or4% HSA, by the following procedure. Membranes (1.25 μg/well for 0.1% BSAand 6 μg/well for 1% or 4% HSA) were mixed with ³H-labeled PGD₂ andvarious concentrations of test compounds in 150 μL of binding buffer (50mM Tris-HCl, pH 7.4, 40 mM MgCl₂, 0.1% bovine serum albumin, 0.1% NaN₃)in 96-well U-bottom polypropylene plates. After incubation for 60minutes at room temperature, the assay was transferred to a filtrationplate (#MAFB; Millipore Corporation, Bedford, Mass.), and washed threetimes with binding buffer. Radioactivity was measured by a scintillationcounter (TopCount; PerkinElmer Life Sciences, Boston, Mass.).Nonspecific binding was determined by incubations in the presence of 1μM unlabeled PGD₂ or 5 μM of a known DP2 antagonist. EC₅₀ values forinhibition of binding were determined for each compound tested from theinflexion point of a standard 4-parameter logistical curve fitted to thevalues obtained. Compounds of the invention had EC₅₀ values less than 5micromolar in one or more of the binding assays. Certain compounds ofthe invention had EC₅₀ values less than 1 micromolar in one or more ofthe binding assays. Certain compounds of the invention had EC₅₀ valuesless than 0.5 micromolar in one or more of the binding assays. Certaincompounds of the invention had EC₅₀ values less than 0.25 micromolar inone or more of the binding assays.

When certain compounds of the invention prepared as racemic mixtureswere separated to isolate each enantiomer, it was found that oneenantiomer was more potent than the other enantiomer when tested in aDP2 binding inhibition assay as described above.

EC₅₀ values for compounds of the invention when tested in a DP2 bindinginhibition assay as described above are provided in Table A.

TABLE A EC₅₀ (nM) EC₅₀ (Nm) EC₅₀ (nM) Ex. # 4% HSA 1% HSA 0.1% BSA 1400.1 16.6 2 70 3 5000 129.4 4 10.7 5 37.4 6 77.3 7 19 8 16 9 203 10 22513.9 11 110.6 9.3 Enantiomer 2 12 794.3 13 404.6 14 824.1 15 746.4 16318 17 395 18 502 19 638.3 20 758.6 21 169 22 438.5 23 326.6 24 481.9 253334 26 160.3 27 215.8 28 122.7 29 136.8 30 300.6 31 91.4 32 88 33 12634 73.1 10.5 35 64.3 36 93.05 17.3 37 55 12 38 365.6 39 68.2 40 42.2 41150.3 42 73.8 43 51.5 44 3475.4 45 1374 46 176.2 15.8 47 12.1 48 30.7 4922.5 50 11 51 14.8 12.1 52 90.8 53 60.5 54 109.1 55 12.1 56 14.2 57 18.958 434.5 59 157.8 60 131.2 61 920.4 62 88.5 63 304.8 64 153.1 65 80.4 6668.2 67 172.6 68 206.1 69 239.9 70 995.4 71 119.1 72 36.4 73 42.4 7423.3 75 11.9 76 6.7 77 356.5 78 680.8 79 98.9 80 165.2 81 191.4 82 473.283 568.9 84 1380.4 85 344.3 86 126.5 87 233.9 88 202.8 89 145.5 90 152.891 192.3 92 111.2 93 106.7 94 287.1 95 91.8 96 40.2 97 190.1 98 193.2 9950.7 5.1 100 619.4 101 292.4 102 48.9 7.7 103 391.7 104 955 105 107.4106 62.7 2.65 Enantiomer 2 106 >5000 Enantiomer 1 107 115.3 108 69.3 109103.8 110 606.7 111 173.8 112 4187.9 113 2382.3 114 91 115 2437.8 116304.1 117 246 118 425.6 119 206 120 371 121 4315 122 242 123 259 124 841125 420.7 126 179.1 127 270.4 128 979.5 107.6 129 21.9 130 25.7 131 59.3132 37.4 133 625.2 134 112.5 135 204.6 136 4217 137 120.5 138 239.3 139226.5 140 497.7 141 1000 142 139.6 143 1009.3 144 87.9 16.4 145 654.6146 608.1 147 239.9 148 196.3 149 280.5 150 341.2 151 342.8 152 159.6153 521.2 154 485.3 155 399 peak 1 155 1671.1 peak 2 156 509.3 1571584.9 158 1648.2 159 663.7 160 349.9 161 1116.9 162 429.5 163 509.3 164183.2 165 400.9 166 272.3 167 179.1 168 302 169 204.2 170 297.9 171332.7 172 281.8 173 327.3 174 722.8 175 571.5 176 338.8 177 163.3 1781733.8 179 1112 180 407 181 331.1 182 151.4 183 968.3 184 824.1 185 857186 538 187 649 188 758.6 189 196.8 190 922.6 191 164.1 192 191 193639.7 194 3006 195 1145.5 196 269.2 197 688.7 198 68.1 199 110.7 200331.1 201 137.7 202 71.6 203 103 204 196.3 205 94 206 64 207 26.4 20841.4 209 57.7 210 54.1 211 37.2 212 81.5 213 45.1 214 94.2 215 58.2 216493.2 217 180.3 218 143.9 219 1039 220 >2000 221 45 222 118 223 209 224373 225 56 226 88.5 227 74.5 228 88.9 229 67.5 230 243 231 225.4 23246.5 233 11.1 234 21.7 Enantiomer 2 234 >5000 Enantiomer 1 235 17Enantiomer 2 235 >5000 Enantiomer 1 236 34 Enantiomer 2 236 1361Enantiomer 1 237 25.6 Enantiomer 2 237 >5000 Enantiomer 1 238 16.2Enantiomer 2 239 48.1 Enantiomer 2 239 367 Enantiomer 1

EXAMPLE B Mouse Allergic Rhinitis Model

Allergic rhinitis (AR) is the most common form of atopic disease with anestimated prevalence ranging from 5% to 22% (Naclerio, R. M., N. Engl.J. Med. 1991, 325:860-869), leading to enormous associated costs fortreatment. The typical symptoms of AR in human subjects are well known,mainly sneezing and nasal blockage (Corrado O. J., et al., Br. J. Clin.Pharmacol. 1987, 24:283-292; Mygind N and Anggard A. Clin. Rev. Allergy,1984, 2:173-188). The 3 major causes of the nasal blockage are thoughtto be dilatation of capacitance vessels in the nasal septum andturbinates, edematous swelling of nasal membranes, and the direct resultof secretions (Sherwood J. E., et al. J. Allergy Clin. Immunol., 1993,92:435-441; Juliusson S. and Bende M., Clin Allergy 1987, 17:301-305;Mygind N. et al., Eur J Respir Dis Suppl. 1987, 153:26-33; Gawin A. Z.,et al., J Appl Physiol. 1991, 71:2460-2468).

Nasal reactivity in AR has been shown to occur in 2 phases: early-phaseand late-phase responses. Early-phase responses occur within minutes ofexposure to the allergen and tend to produce sneezing, itching, andclear rhinorrhea; the late-phase response reaction occurs 6 to 24 hoursafter local allergen challenge of subjects with atopic rhinitis and ischaracterized by congestion, fatigue, malaise, and irritability(Naclerio, supra). Persistent tissue edema and eosinophils, mast cells,TH2-type lymphocytes, and macrophages are thought to be involved(Naclerio, supra).

Methods

Ovalbumin (OVA) Sensitization and Nasal Challenge

Balb/c mice were obtained from Jackson Laboratories (Bar Harbor, Me.).Animals were housed under conventional conditions and maintained on anOVA-free diet. Female mice, 6-12 weeks of age, were used in all studies.All experimental animals used in these studies were under a protocolapproved by the Institutional Animal Care and Use committee. Mice weresensitized by an intraperitoneal injection of 20 μg of OVA (Grade V;Sigma Chemical, St Louis, Mo.) emulsified in 2.25 mg of alum(AlumImuject; Pierce, Rockford, Ill.) in a total volume of 100 μL ondays 0 and 14. Two weeks following sensitization, mice received dailychallenges of OVA (10% in saline) by instillation in the nostril withoutanesthesia for 6 days. Animals were dosed either on day 4 or on each ofdays 1-6 with a compound of the invention at a dose between 0.1-10 mg/kgone hour before nasal challenge.

Measurement of Respiratory Parameters with Whole-Body Plethysmography

Respiratory frequency (RF), expiratory time, and inspiratory time weremeasured in unrestrained conscious animals by using single-chamberwhole-body plethysmography (WBP; Buxco, Troy, N.Y.). Before themeasurement, mice were left in the chambers for 20 minutes with constantairflow. For measurement of respiratory parameters during theearly-phase reaction (4^(th) nasal challenge), mice received OVA (20 μLof 25 mg/mL) through the nostril after measurement of baseline valuesand were then placed back into the box. RF, inspiratory time, andexpiratory time were measured.

Measurement of Nasal Resistance

For resistance, measurements of piston volume displacement and cylinderpressure were used to calculate the impedance of the respiratory system,as described by Pillow et al. (J Appl Physiol. 2001, 91:2730-2734).Briefly, each muse was anesthetized with pentobarbital sodium (50 mg/kgadministered intraperitoneally) and fixed in a supine position.Tracheostomized (18-gauge cannula) mice were mechanically ventilated(160 breaths/minute, tidal volume to 0.15 mL). The frontal and rightlateral walls of the upper trachea and larynx were removed. Afterincision of the frontal wall of the pharynx, a blunt 19-gauge needle wascarefully inserted into the nasopharynx through the pharynx. The needlewas connected to a polyethylene tube (outer diameter, 0.165 cm) with a2-mm overhang. The other end of the tube was connected to acustom-designed ventilator. The nasal cavity was ventilated with 8 mL/kgat a rate of 150 breaths/minute. Resistance was determined by measuringthe piston volume displacement and cylinder pressure. Resistance of thelate-phase response (persistent nasal obstruction) was measured 24 hoursafter the last OVA challenge. All data were analyzed with FlexiVentsoftware (Scireq, Montreal, Quebec, Canada).

Compounds described herein were shown or will be shown to be effectivein this model.

Preparation 1 4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid

Step A: Preparation of3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one: A 2-liter 4-neckround-bottom flask was charged with trifluoromethanesulfonic acid (500g, 3.33 mol) and the flask contents were cooled below 10° C.4-Chlororesorcinol (100 g, 0.69 mol) was added in portions over 20-30minutes, maintaining the temperature at 4 to 8° C. The reaction mixturewas stirred at or below 10° C. until a clear solution formed (40minutes). 3-Chloropropanoic acid (78.8 g, 0.73 mol) was warmed untilmelted and then added in liquid form dropwise over 45 minutes to theflask, maintaining the temperature at or below 10° C. The reactionmixture was stirred for an additional 10 minutes at or below 10° C.,then slowly heated to 50-55° C. and maintained there for 6 hours. Thereaction mixture was cooled to ambient temperature and added dropwise towater (1.1 L) contained in a 3-liter 4-neck round-bottom flask. Theresulting mixture was stirred at ambient temperature for 30 minutes. Theresulting precipitate was collected by filtration, washed with water(3×540 mL), and dried in a fan dryer at 40° C. until the moisturecontent fell below 0.5%, to afford3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one as an orange solid(160 g, 98.4% yield).

Step B: Preparation of 6-chloro-7-hydroxychroman-4-one: A 20-liter4-neck round-bottom flask was charged with water (10 L) and3-chloro-1-(5-chloro-2,4-dihydroxyphenyl)propan-1-one (1.62 kg, 6.89mol), and the resulting mixture was stirred and cooled to 10° C. Asolution of sodium hydroxide (606.5 g, 15.16 mol) in water (2.96 L) wasadded dropwise over 40-60 minutes, maintaining the temperature at 10-15°C. The resulting mixture was stirred at ambient temperature for afurther 30 minutes, then cooled to 5° C. Concentrated hydrochloric acid(1.31 L, 15.98 mol) was added dropwise over 30 minutes, maintaining thetemperature at or below 10° C. The resulting mixture was stirred atambient temperature for a further 30 minutes, and the resultingprecipitate was collected by filtration, washed with water (3×5.5 L),and dried at 40° C. until the moisture content fell below 1%. This crudeproduct (1.2 kg) was transferred to a 10-liter 4-neck round-bottom flaskand stirred with acetonitrile (6.0 L) at ambient temperature for 2hours, then cooled to 0-5° C. and stirred for an additional 2 hours. Theresulting precipitate was collected by filtration, washed with 4:1water:acetonitrile (1.5 L) and water (1.2 L), and dried in a fan dryerat 40° C. until the moisture content fell below 0.5%, to afford6-chloro-7-hydroxychroman-4-one as an off-white solid (858 g, 62.7%yield).

Step C: Preparation of6-chloro-4,7-bis(trimethylsilyloxy)chroman-4-carbonitrile: (CAUTION:Hydrogen cyanide gas is produced in this reaction; take appropriateprecautions). A 20-liter 4-neck round-bottom flask was charged withdichloromethane (12.5 L), iodine (32 g, 0.13 mol) and6-chloro-7-hydroxychroman-4-one (1.25 kg, 6.30 mol). The resultingmixture was stirred under nitrogen and cooled to 10° C. Trimethylsilylcyanide (2.36 L, 18.88 mol) was added dropwise over 30 minutes,maintaining the temperature at or below 10° C. The reaction mixture wasstirred at ambient temperature for 10-11 hours, then cooled below 20° C.A solution of sodium thiosulfate (59.5 g, 0.38 mol) in water (500 mL)was added dropwise, maintaining the temperature below 20° C., and theresulting mixture was stirred for 20 minutes while maintaining thetemperature below 20° C. Solid sodium sulfate anhydrous (3.75 kg) wasadded, and the resulting mixture was stirred for 30 minutes whilemaintaining the temperature below 20° C. The reaction mixture wasfiltered through a HyFlo™ bed, and the bed was washed withdichloromethane. The combined filtrate and washing were concentratedunder reduced pressure at a temperature below 50° C. to afford6-chloro-4,7-bis(trimethylsilyloxy)chroman-4-carbonitrile as a brown oil(2.2 kg, 94.5% yield).

Step D: Preparation of 6-chloro-7-hydroxychroman-4-carboxylic acid: A20-liter 4-neck round-bottom flask was charged with glacial acetic acid(2.04 L), 6-chloro-4,7-bis(trimethylsilyloxy)chroman-4-carbonitrile (2.2kg, 5.94 mol), and tin(II) chloride dihydrate (3.35 kg, 14.85 mol) andthe resulting mixture was stirred at ambient temperature. Concentratedhydrochloric acid (5.0 L, 60 mol) was added, and the resulting mixturewas stirred and heated to 80-85° C. for 12 hours. The reaction mixturewas cooled to ambient temperature and water (3.6 L) was added, andstirring was continued at ambient temperature for 15 minutes. Isopropylacetate (11.5 L) and water (5.8 L) were added, and stirring wascontinued at ambient temperature for 15 minutes. The layers wereseparated, and the aqueous layer was extracted with isopropyl acetate(2×2 L). The organic layers were combined and washed with brine (3×6 L),then dried over sodium sulfate and concentrated under reduced pressureat a temperature below 50° C. to afford crude6-chloro-7-hydroxychroman-4-carboxylic acid as a brown semi-solid (1.70kg, 125% yield).

Step E: Preparation of ethyl 6-chloro-7-hydroxychroman-4-carboxylate: A20-liter 4-neck round-bottom flask was charged with ethanol (8.6 L) andcrude 6-chloro-7-hydroxychroman-4-carboxylic acid (1.70 kg, 7.44 mol)and the resulting mixture was stirred at ambient temperature.Concentrated sulfuric acid (397 mL) was added over 10 minutes. Theresulting mixture was stirred and heated to reflux for 16 hours. Thereaction mixture was cooled to ambient temperature and diluted withethyl acetate (9.0 mL). The resulting mixture was washed with brine(2×12 L). The brine washes were combined and extracted with ethylacetate (4 L). The ethyl acetate layer was washed with brine (2 L). Theorganic layers were combined and dried over sodium sulfate, thenconcentrated under reduced pressure at a temperature below 50° C. Theresidue was purified by chromatography on silica gel (18 kg), elutingwith 85:15 hexanes:ethyl acetate (235 L), to afford ethyl6-chloro-7-hydroxychroman-4-carboxylate as a white powder (822 g, 43%yield). MS (apci) m/z=255.1 (M−H).

Step F: Preparation of ethyl7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate:Tert-butyl 4-bromobenzoate (210.4 g, 818.2 mmol) was dissolved in 1 L ofdioxane, which was previously degassed with argon, in a 4-neck 5 L roundbottom flask equipped with a mechanical stirrer and a reflux condenser.Under argon flow and with stirring, ethyl6-chloro-7-hydroxychroman-4-carboxylate (176.4 g, 687.2 mmol),N,N-dimethyl glycine hydrochloride (35.7 g, 346.2 mmol) and cuprouschloride (34.0 g, 342.9 mmol) were added via a funnel. Cesium carbonatethen added and an additional 0.5 L of dioxane was added to the reactionmixture. The mixture was then heated at 95-97° C. for 20 hours. Aftercooling to ambient temperature, the reaction mixture was poured into 3 Lof a 3:1 mixture of hexanes:ethyl acetate and activated charcoal (300 g)was added. After stirring periodically for 1 hour, the mixture wasfiltered thru GF/F paper, washing the filter cake with 2 L of a 3:1mixture of hexanes:ethyl acetate. The resulting golden brown solutionwas concentrated to provide 304 g of crude ethyl7-(4-(tert-butoxycarbonyl)-phenoxy)-6-chlorochroman-4-carboxylate. Thecrude product was dissolved in dichloromethane, concentrated onto silicagel and purified by flash column chromatography, eluting with a gradientof 10 to 25% ethyl acetate in hexanes to give ethyl7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate as acolorless, viscous oil (221 g, 74.3% yield). ¹H NMR (400 MHz, CDCl₃) δ7.96 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 6.94 (d, J=8.8 Hz, 2H), 6.54 (s,1H), 4.21-4.29 (m, 4H), 3.74 (t, J=5.3 Hz, 1H), 2.30-2.36 (m, 1H),2.05-2.14 (m, 1H), 1.58 (s, 9H), 1.31 (t, J=7.0 Hz, 3H).

Step G: Preparation of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid: Ethyl7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (221 g,0.511 mol) was dissolved in hydrogen chloride in ethyl acetate (2.4 N,1.6 L, 3.84 mol) and the resulting solution was stirred at ambienttemperature for 16 hours. The solution was concentrated to give 198 g ofcrude 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)-benzoic acid. Thecrude product was recrystallized by dissolving in hot isopropyl acetate(0.5 L) and diluting with hexanes (1.1 L). After 48 hours, the crystalswere collected and wash with hexanes. The resulting white solids weredried under high vacuum to give4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (169 g, 88%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=8.9 Hz, 2H), 7.38 (s, 1H),6.98 (d, J=8.8 Hz, 2H), 6.60 (s, 1H), 4.21-4.31 (m, 4H), 3.75 (t, J=5.4Hz, 1H), 2.31-2.37 (m, 1H), 2.08-2.15 (m, 1H), 1.32 (t, J=7.0 Hz, 3H).

Preparation 2 4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid

Step A: Preparation of methyl7-(4-(tert-butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate: A 500ml flask equipped with a Claisen head and a condenser was charged withoven dried MS 4A powder (14.5 g), methyl6-cyano-7-fluorochroman-4-carboxylate (14.11 g, 60.00 mmol), tert-butyl4-hydroxybenzoate (14.57 g, 75.00 mmol), K₂CO₃ (20.73 g, 150.0 mmol),and 1-methyl-2-pyrrolidinone (120 mL). The mixture was degassed withArgon for 1 hour, then heated to 115° C. for 18 hours. The mixture wascooled to ambient temperature. The mixture was filtered through a CELITEpad and rinsed with EtOAc. The combined filtrates were washed withwater. The EtOAc layer was dried over MgSO₄, filtered through GF paper,and concentrated to a crude oil. The crude oil was purified on silicagel (EtOAc in hexanes gradient) to provide 18.5 g of the desiredcompound as semisolid.

Step B: Preparation of4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid:7-(4-(tert-Butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate (18.5 g,45.185 mmol) was dissolved in dichloromethane (200 mL). Trifluoroaceticacid (50 mL) was added and the mixture was stirred at ambienttemperature for 1.5 hours, and then concentrated under reduced pressureto provide a crude solid. The solid was dissolved in EtOAc (200 ml), andhexanes (600 ml) were added with stirring. White solid was crashed outand was collected by filtration to provide 13.11 g of the desiredcompound as white solid (81.9%). The mother liquor was concentrated andthe residue was dissolved in EtOAc (25 ml). Hexanes (100 ml) were addedwith stirring and a white solid was crashed out and was collected byfiltration to provide an additional 1.14 g of the desired compound.

Preparation 3 Methyl6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate

A 50 ml round bottomed flask was charged with4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation2) (1.466 g, 4.15 mmol), a drop of DMF, and 1,2-dichloroethane (10 ml).Oxalyl chloride (2M in dichloromethane) (2.283 ml, 4.565 mmol) wasslowly added and the mixture became a clear solution. Gas evolution wasobserved. The mixture was stirred for 17 hours at ambient temperature.Triethylamine (1.157 ml, 8.30 mmol) and 3-iodoaniline (0.524 ml, 4.358mmol) were added to the acid chloride solution. The mixture was stirredfor 1 hour at ambient temperature. The crude mixture was purified onsilica gel (EtOAc in hexanes gradient) to provide 2.094 g of the titlecompound as light brown solid (91%).

Preparation 4 Ethyl 6-chloro-7-hydroxychroman-4-carboxylate

Step A: Preparation of 6-chloro-7-hydroxychroman-4-one: A 50-literreactor was charged with trifluoromethanesulfonic acid (8 kg) and thereactor cooled in an ice bath. To the reactor was added4-chlororesorcinol (1.6 kg, 11.1 mol), in portions, at a rate such thatthe internal temperature did not exceed 10° C. To the reactor was thenadded 3-chloropropanoic acid (1.26 kg, 11.6 mol), and the resultingmixture was warmed to ambient temperature, then heated at 45-55° C. for6 hours. The reaction mixture was then slowly added to ice-water (20 L).The resulting slurry was stirred for 2 hours, and the resultingprecipitate was collected by filtration, washed with water (12 L), andair-dried. This material was added to a solution of sodium hydroxide(1.1 kg, 27.5 mol) in ice-water (24 L), at a rate such that the internaltemperature did not exceed 20° C. The resulting solution was stirredbelow 20° C. for 1 hour, then cooled, and treated with concentratedhydrochloric acid (2.5 L), at a rate such that the temperature did notexceed 10° C. The resulting slurry was stirred below 10° C. for 1 hour,and the resulting precipitate was collected by filtration, washed withwater (10 L), and partially air-dried. The crude solids from four suchprocedures were combined and added to a mixture of acetone (32 L) andwater (40 L), and the resulting mixture was stirred and heated until aclear solution formed. This solution was then cooled to 5-10° C., andthe resulting precipitate was collected by filtration, washed with water(12 L), and dried to afford 6-chloro-7-hydroxychroman-4-one as a whitesolid (4.6 kg, 52% yield).

Step B: Preparation of 6-chloro-7-hydroxychroman-4-carboxylic acid,dicyclohexylamine salt: (CAUTION: Hydrogen cyanide gas is produced inthis reaction; take appropriate precautions). A 10-liter 4-neckround-bottom flask equipped with a reflux condenser, mechanical stirrer,and thermometer was charged with 6-chloro-7-hydroxychroman-4-one (1.5kg, 7.6 mol), zinc iodide (49.0 g, 0.154 mol), and trimethylsilylcyanide (2.5 L, 20.0 mol), under an atmosphere of nitrogen. Theresulting mixture was stirred at 45-50° C. for 2 hours, then cooled toambient temperature and treated successively with a solution of sodiumthiosulfate (2.5 kg) in water (6 L), saturated sodium bicarbonatesolution (2 L), and ethyl acetate (5 L). The resulting mixture wasstirred at ambient temperature for 30 minutes. The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (2 L).The organic layers were combined and washed with saturated sodiumbicarbonate solution (1 L) and brine (2×1 L), then concentrated underreduced pressure. To the resulting brown oil was added was addedsuccessively tin(II) chloride dihydrate (5.3 kg, 23.5 mol), concentratedhydrochloric acid (7.5 L) and glacial acetic acid (2.7 L). The resultingmixture was stirred and heated to reflux (100° C.) for 18 hours, thencooled to ambient temperature. The resulting orange precipitate wasremoved by filtration, and the filtrate was treated with dichloromethane(5 L). After stirring for 20 minutes, solid sodium chloride was addeduntil the aqueous layer was saturated. The layers were separated, andthe aqueous layer was extracted with dichloromethane (2×2 L). Theorganic layers were combined and washed with brine (1 L), then treatedwith 10% aqueous sodium hydroxide until the apparent pH of the organiclayer was 10-11. The aqueous layer was acidified with concentratedhydrochloric acid to pH 3-4, then extracted with ethyl acetate (3×2 L).The organic layers were combined and stirred at ambient temperature, anddicyclohexylamine (1.5 L) was added dropwise. The resulting mixture wasstirred at ambient temperature for 1 hour, and the resulting precipitatewas collected by filtration, washed with ethyl acetate (2×1 L), anddried to afford 6-chloro-7-hydroxychroman-4-carboxylic acid,dicyclohexylamine salt as an off-white solid (2.0 kg, 64% yield).

Step C: Preparation of ethyl 6-chloro-7-hydroxychroman-4-carboxylate: A10-liter 4-neck round-bottom flask equipped with a reflux condenser,mechanical stirrer, and thermometer was charged with6-chloro-7-hydroxychroman-4-carboxylic acid, dicyclohexyl-amine salt(1.7 kg, 4.1 mol) and 10% aqueous sodium hydroxide (4 L). The resultingmixture was extracted with methyl tert-butyl ether (2×1 L). The aqueouslayer was acidified to pH 2-3 with concentrated hydrochloric acid, thenextracted with ethyl acetate (2×2 L). The organic layers were combinedand dried over magnesium sulfate, then concentrated under reducedpressure. The residual free acid was dissolved in ethanol (4.5 L) and tothe resulting solution was added concentrated sulfuric acid (240 mL),dropwise. The resulting solution was stirred and heated to reflux for 16hours. After cooling to ambient temperature, the solution was dilutedwith water (1.5 L), followed by dropwise addition of saturated sodiumbicarbonate solution (3 L), resulting in an apparent pH of about 3. Theresulting mixture was stirred for 5 hours at ambient temperature, andthe resulting precipitate was collected by filtration, washed with water3 L), and dried to afford ethyl 6-chloro-7-hydroxychroman-4-carboxylateas a light pink powder (850 g, 81% yield). MS (apci) m/z=255.1 (M−H).

Preparation 5 2-(2-Bromo-4-chlorophenyl)ethanamine

Step A: Preparation of 2-bromo-4-chloro-1-(dibromomethyl)benzene: To astirred solution of 4-bromo-2-chlorotoluene (10.0 g; 48.7 mmol) andbenzoyl peroxide (0.51 g; 2.09 mmol) in 80 mL of carbon tetrachloridewas added N-bromosuccinimide (43.3 g; 243 mmol), and the resultingmixture was stirred and heated to reflux. After 15 hours, the mixturewas cooled to ambient temperature, and the insoluble material wasremoved by filtration and washed twice with carbon tetrachloride. Thefiltrate and washings were combined and evaporated. The residue waspurified by silica gel chromatography on a Biotage 65M column, elutingwith hexanes to give 17.4 g of 2-bromo-4-chloro-1-(dibromomethyl)benzeneas a colorless liquid.

Step B: Preparation of 2-bromo-4-chlorobenzaldehyde: A solution of2-bromo-4-chloro-1-(dibromomethyl)benzene (17.4 g; 47.9 mmol) in 25 mLethanol was stirred and heated to reflux, and a solution of silver(I)nitrate (76.1 g; 448 mmol) in 55 mL water was added dropwise over 20minutes. The mixture turned yellow and a precipitate of AgBr formedimmediately upon addition. Following completion of addition, the mixturewas stirred at reflux for an additional hour. After reaching ambienttemperature, the mixture was diluted with 200 mL water and filtered toremove insoluble material. The filtrate was extracted with 200 mLchloroform and the insoluble materials were washed with 2×200 mLchloroform. The chloroform layers were combined and washed with 250 mLwater, then dried over sodium sulfate and evaporated to give 10.3 g of2-bromo-4-chlorobenzaldehyde as a white solid.

Step C: Preparation of 2-bromo-4-chloro-1-(2-nitrovinyl)benzene: Asuspension of 2-bromo-4-chlorobenzaldehyde (2.2 g; 10.0 mmol),methylamine hydrochloride (0.43 g; 6.4 mmol) and sodium acetate (0.53 g;6.4 mmol) in 3.8 mL of nitromethane (70.1 mmol) was stirred at ambienttemperature. After stirring for 19 hours the mixture was diluted with 20mL water and 40 mL dichloromethane, and the mixture was transferred to aseparatory funnel. After shaking, the organic layer was separated, driedover sodium sulfate and evaporated to give 2.56 g of a light brownsolid. The crude material was purified by silica gel chromatography on aBiotage 40S column, eluting with 95/5 hexane/EtOAc to give 1.18 g of2-bromo-4-chloro-1-(2-nitrovinyl)benzene as a light yellow solid. MS(apci, neg) m/z=261.

Step D: Preparation of 2-(2-bromo-4-chlorophenyl)ethanamine: To astirred suspension of lithium borohydride (0.39 g; 18.0 mmol) in 25 mLTHF at ambient temperature was added chlorotrimethylsilane (3.9 g; 36.0mmol), dropwise over 2 minutes. Gas was evolved and the mixture warmedslightly. After stirring for 20 minutes, gas evolution had ceased, andargon gas was bubbled through the mixture for 2 minutes to try to removethe remaining trimethylsilane that had formed. A solution of2-bromo-4-chloro-1-(2-nitrovinyl)benzene (1.18 g; 4.5 mmol) in 20 mLtetrahydrofuan was then added dropwise with stirring at ambienttemperature over 4 minutes. The resulting mixture was stirred and heatedto reflux. After 2 hours, the heat was removed, and after cooling toambient temperature, the mixture was cooled in an ice bath and carefullyquenched with 25 mL methanol. The solvent was evaporated, and theresidue was partitioned between 50 mL of 20% KOH and 25 mL ofdichloromethane. The organic layer was dried over sodium sulfate andevaporated to give 0.92 g of 2-(2-bromo-4-chlorophenyl)ethanamine as acloudy yellow oil. MS (apci, pos) m/z=234.

Preparation 6 2-(2-Methoxy-4-bromophenyl)ethanamine

Step A: Preparation of 4-bromo-2-methoxybenzaldehyde: To a stirredsolution of 4-bromo-2-fluorobenzaldehyde (3.38 g; 16 mmol) in 35 mLmethanol at ambient temperature was added sodium methoxide solution (4.0mL of 25% solution; 17.6 mmol), and the resulting solution was stirredand heated to reflux. After refluxing for 2 hours the solvent wasevaporated. The residue was partitioned between 100 mL dichloromethaneand 50 mL water. The organic layer was dried over sodium sulfate andevaporated. The residue was purified by silica gel chromatography togive 2.13 g of 4-bromo-2-methoxybenzaldehyde as a white solid. MS (apci,neg) m/z=199.

Step B: Preparation of 4-bromo-2-methoxy-1-(2-nitrovinyl)benzene: Asuspension of 4-bromo-2-methoxybenzaldehyde (1.55 g; 7.2 mmol),methylamine hydrochloride (0.31 g; 50.4 mmol) and sodium acetate (0.38g; 4.6 mmol) in 3 mL of nitromethane was stirred at ambient temperature.After stirring for 14.5 hours the mixture was diluted with 20 mL waterand 40 mL dichloromethane, and the mixture was transferred to aseparatory funnel. After shaking, the organic layer was dried oversodium sulfate and evaporated to give 1.74 g of4-bromo-2-methoxy-1-(2-nitrovinyl)benzene as a light yellow solid. MS(apci, neg) m/z=257.

Step C: Preparation of 2-(4-bromo-2-methoxyphenyl)ethanamine: To astirred suspension of lithium borohydride (0.57 g; 26.3 mmol) in 40 mLtetrahydrofuran at ambient temperature was added chlorotrimethylsilane(5.7 g; 52.7 mmol), dropwise over 2 minutes. Gas was evolved and themixture warmed slightly. After stirring for 20 minutes, gas evolutionhad ceased, and argon gas was bubbled through the mixture for 2 minutesto try to remove the remaining trimethylsilane that had formed. Asolution of 4-bromo-2-methoxybenzaldehyde (1.7 g; 6.6 mmol) in 30 mLtetrahydrofuran was then added dropwise with stirring at ambienttemperature over 4 minutes. The resulting mixture was then stirred andheated to reflux. After 90 minutes, the heat was removed, and aftercooling to ambient temperature, the mixture was cooled in an ice bathand carefully quenched with 40 mL methanol. The solvent was evaporated,and the residue was partitioned between 80 mL of 20% KOH and 40 mL ofDCM. The organic layer was dried over sodium sulfate and evaporated togive 1.29 g of 2-(4-bromo-2-methoxyphenyl)ethanamine as a dark greenoil. MS (apci, pos) m/z=230.

Preparation 7 2-(2,4-Dichloro-6-methoxyphenyl)ethanamine

Step A: Preparation of 2,4-dichloro-6-methoxybenzaldehyde: To a stirredsolution of 2,4-dichloro-6-hydroxybenzaldehyde (1.85 g; 9.7 mmol) in 20mL DMF at ambient temperature was added solid potassium carbonate (1.47g; 10.6 mmol), and the resulting yellow mixture was stirred at ambienttemperature. After 30 minutes, iodomethane (5.5 g; 38.7 mmol) was added,and the resulting mixture was stirred in an oil bath set to 50° C. After10 minutes, the reaction was determined to be complete by thin layerchromatography (90/10 hexane/EtOAc). After a total of 30 minutes themixture was cooled to ambient temperature and diluted with 200 mL water.After stirring for a few minutes, the precipitate that formed wascollected by filtration, washed with water, and dried under vacuum togive 1.93 g of 2,4-dichloro-6-methoxybenzaldehyde as an off-whitepowder.

Step B: Preparation of 1,5-dichloro-3-methoxy-2-(2-nitrovinyl)benzene: Asuspension of 2,4-dichloro-6-methoxybenzaldehyde (0.51 g; 2.5 mmol),methylamine hydrochloride (0.11 g; 1.6 mmol) and sodium acetate (0.13 g;1.6 mmol) in 3 mL of nitromethane was stirred at ambient temperature.After stirring for 15.5 hours the mixture was diluted with 20 mL waterand 40 mL DCM, and then transferred to a separatory funnel. Aftershaking, the organic layer was dried over sodium sulfate and evaporatedto give 0.57 g of 1,5-dichloro-3-methoxy-2-(2-nitrovinyl)benzene as alight yellow solid. MS (apci, neg) m/z=247

Step C: Preparation of 2-(2,4-dichloro-6-methoxyphenyl)ethanamine: To astirred suspension of lithium borohydride (0.20 g; 9.0 mmol) in 15 mLtetrahydrofuran at ambient temperature was added chlorotrimethylsilane,dropwise over 2 minutes. Gas was evolved and the mixture warmedslightly. After stirring for 20 minutes, gas evolution had ceased, andargon gas was bubbled through the mixture for 2 minutes to remove theremaining trimethylsilane that had formed. A solution of1,5-dichloro-3-methoxy-2-(2-nitrovinyl)benzene (0.56 g; 2.3 mmol) in 10mL THF was then added dropwise with stirring at ambient temperature over4 minutes. The resulting mixture was then stirred and heated to reflux.After 90 minutes, the heat was removed, and after cooling to ambienttemperature, the mixture was cooled in an ice bath and carefullyquenched with 15 mL of methanol. The solvent was evaporated, and theresidue was partitioned between 30 mL of 20% KOH and 15 mL ofdichloromethane. The organic layer was dried over sodium sulfate andevaporated to give 0.49 g of 2-(2,4-dichloro-6-methoxyphenyl)ethanamineas a cloudy yellow oil. MS (apci, pos) m/z=220.

Preparation 8 2-(4-Chloro-2-methoxyphenyl)ethanamine

Step A: Preparation of 2-bromo-4-chloro-1-(dibromomethyl)benzene: To astirred solution of 4-bromo-2-chlorotoluene (100 g; 487 mmol) andbenzoyl peroxide 5.07 g; 20.9 mmol) in 800 mL of carbon tetrachloridewas added N-bromosuccinimide, and the resulting mixture was stirred andheated to reflux. After 16.5 hours, the mixture was cooled to ambienttemperature, and the insoluble material was removed by filtration andwashed twice with carbon tetrachloride. The filtrate and washings werecombined and evaporated. The orange residual liquid contained somesolid, and this material was taken up in 500 mL hexane. The resultingmixture was filtered to remove insoluble material, and the filtrate wasitself filtered through a 1 inch pad of silica gel in a 150 mL fittedfunnel. The filtrate was evaporated to give 161.5 g of2-bromo-4-chloro-1-(dibromomethyl)benzene as a pale yellow liquid.

Step B: Preparation of 2-bromo-4-chlorobenzaldehyde: A solution of2-bromo-4-chloro-1-(dibromomethyl)benzene (162 g; 446 mmol) in 250 mLethanol was stirred and heated to reflux, and a solution of silver(I)nitrate (576 g; 3.39 mol) in 600 mL water was added dropwise over 40minutes. The mixture turned yellow and a precipitate of AgBr formedimmediately upon addition. Following completion of addition, the mixturewas stirred at reflux for an additional hour. After reaching ambienttemperature, the mixture was filtered through a sintered glass funnel tocollect the precipitate, which was then washed with 200 mL water. Theprecipitate was washed with 500 mL chloroform. The washes were combinedand transferred to a separatory funnel and the water contained wasallowed to separate. The organic layer was dried over sodium sulfate andevaporated to give 93.3 g of 2-bromo-4-chlorobenzaldehyde as a whitesolid.

Step C: Preparation of (2-bromo-4-chlorophenyl)methanol: A solution of2-bromo-4-chlorobenzaldehyde (21.95 g; 100.0 mmol) in 200 mL methanolwas stirred and cooled in an ice bath for 15 minutes, and solid sodiumborohydride (1.9 g; 50.0 mmol) was added. A yellow color formed andthere was copious gas evolution. Stirring was continued in the bath for1 hour. The solution was diluted with 200 mL water, and then themethanol was evaporated on a rotary evaporator. The residual mixture wasextracted with 200 mL EtOAc. The organic layer was washed with 50 mLbrine, then dried over sodium sulfate and evaporated. The residual solidwas washed out of the flask with hexane and collected by filtration,ground with a mortar and pestle to break up the chunks, then washed withhexane and air-dried on the filter to give 17.8 g of(2-bromo-4-chlorophenyl)methanol as a white solid.

Step D: Preparation of 2-bromo-1-(bromomethyl)-4-chlorobenzene: Asolution of (2-bromo-4-chlorophenyl)methanol (17.8 g; 80.4 mmol) in 250mL of ether was stirred and cooled in an ice bath for 15 minutes. Asolution of phosphorus tribromide (21.8 g; 80.4 mmol) in 75 mL ether wasadded, dropwise over 30 minutes. After stirring in the bath for anadditional 30 minutes the solution was quenched by careful addition ofsaturated sodium bicarbonate solution until no more gas was evolved. Theresulting mixture was transferred to a reparatory funnel, and theorganic layer was washed with 50 mL brine, then dried over sodiumsulfate and evaporated to give 21.2 g of pale yellow oil. This materialwas dissolved in a mixture of 100 mL hexane and 25 mL EtOAc. Thissolution was poured over a 2 inch pad of silica gel in a 150 mL frittedfunnel, and the pad was eluted with 2×150 mL hexane. The combinedfiltrates were evaporated to give 10.0 g of2-bromo-1-(bromomethyl)-4-chlorobenzene as a pale yellow oil.

Step E: Preparation of 2-(2-bromo-4-chlorophenyl)acetonitrile: A mixtureof 2-bromo-1-(bromomethyl)-4-chlorobenzene (9.8 g; 34.5 mmol) and sodiumcyanide (2.0 g; 41.4 mmol) in 15 mL of 95% ethanol and 2.5 mL water wasstirred and heated to reflux. After 30 minutes, the solvent wasevaporated and the residue was partitioned between 100 mL ether and 50mL water. The organic layer was dried over sodium sulfate andevaporated. The residual solid was washed out of the flask with hexaneand collected by filtration, washed with hexane, and air-dried on thefilter to give 4.82 g of 2-(2-bromo-4-chlorophenyl)acetonitrile as alight yellow solid.

Step F: Preparation of 2-(4-chloro-2-methoxyphenyl)ethanamine: A portionof 2-(2-bromo-4-chlorophenyl)acetonitrile (7.1 g; 39.1 mmol) wasdirectly dissolved in borane solution (78.2 mL of a 1.0 M solution intetrahydrofuran; 78.2 mmol), and the resulting solution was stirred andheated to reflux. After refluxing for a total of 90 minutes, the heatwas removed and the solution was allowed to cool for a few minutes, andthen 16 mL of methanol was carefully added to quench the solution. Theresulting solution was again heated to reflux for 30 minutes. Thesolvent was then evaporated, and the residue was partitioned between 200mL of 1M HCl (aq.) and 200 mL ether. The aqueous layer was filtered toremove a small amount of suspended insoluble material, and the pH of thefiltrate was adjusted to pH>12 by the addition of 42% NaOH (aq.). Thefiltrate was then extracted with 200 mL dichloromethane. The organiclayer was dried over sodium sulfate and evaporated to give 3.89 g of2-(4-chloro-2-methoxyphenyl)ethanamine as a colorless liquid. MS (apci,pos) m/z=186.

Preparation 9 2-(2-Methoxy-4-(trifluoromethyl)phenyl)ethanamine

Step A: Preparation of 2-methoxy-4-(trifluoromethyl)benzaldehyde:2-Fluoro-4-(trifluoromethyl)benzaldehyde (5.0 g, 26 mmol) was dilutedwith sodium methoxide (57 ml of 0.5 M in methanol; 29 mmol), heated to50° C. and stirred for 6 hours. The reaction was then partiallyconcentrated, diluted with ethyl acetate and water. The layers wereseparated and the organic layer was dried over MgSO₄, filtered andconcentrated to yield 2-methoxy-4-(trifluoromethyl)benzaldehyde (4.5 g,22 mmol, 85% yield).

Step B: Preparation of(E)-2-methoxy-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene: A portion of2-methoxy-4-(trifluoromethyl)benzaldehyde (3.78 g, 18.5 mmol) wasdiluted with nitromethane (7.02 ml, 130 mmol) followed by the additionof methylamine hydrochloride (0.750 g, 11.1 mmol) and sodium acetate(0.911 g, 11.1 mmol). After stirring for 12 hours, the reaction wasloaded directly onto a biotage 40 cartridge and eluted with 5% ethylacetate/hexanes to 20% ethyl acetate hexanes to yield(E)-2-methoxy-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (3.0 g, 12.1mmol, 65.6% yield).

Step C: Preparation of2-(2-methoxy-4-(trifluoromethyl)phenyl)ethanamine: A portion of lithiumborohydride (0.458 g, 21.0 mmol) was diluted with THF (30 mL) followedby the dropwise addition of chlorotrimethylsilane (5.34 ml, 42.1 mmol).After stirring for 15 minutes, argon was bubbled through the reactionmixture for 2 minutes to eliminate trimethylsilane present in thereaction. (E)-2-methoxy-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (1.3g, 5.26 mmol) was added portionwise (gas evolution occurred). Thereaction was heated to reflux for 2 hours, cooled to 0° C. and carefullyquenched with methanol (8 mL). The reaction mixture was concentrated,diluted with dichloromethane and 20% aqueous KOH. The layers wereseparated and the organic layer was dried over sodium sulfate, filteredand concentrated to yield2-(2-methoxy-4-(trifluoromethyl)phenyl)ethanamine (1.1 g, 5.02 mmol,95.4% yield).

EXAMPLE 16-Cyano-7-(4-(4-chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid

Step A: Preparation of7-fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile:7-Fluoro-2,3-dihydrochromen-4-one (470 mg, 2.829 mmol) and ZnI₂ (45.15mg, 0.1414 mmol) was diluted with trimethylsilyl cyanide (1.413 mL,11.32 mmol). The reaction was stirred for 4 hours at ambienttemperature. The reaction was diluted with CH₂Cl₂ and washed withsaturated sodium bicarbonate twice. The organic layer was dried overMgSO₄, filtered and concentrated to yield the title compound (750 mg,99.92% yield).

Step B: Preparation of 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylicacid: 7-Fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile (750 mg, 2.83mmol) and SnCl₂ dihydrate (2551 mg, 11.3 mmol) were diluted with glacialacetic acid (3 mL) and concentrated HCl (3 mL). The reaction was heatedin an oil bath at 130° C. and stirred overnight. The reaction wasallowed to cool, diluted with water and ethyl acetate. The layers wereseparated and the organic layer was dried over MgSO₄, filtered andconcentrated to yield the title compound (465 mg, 83.9% yield).

Step C: Preparation of methyl7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate:7-Fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid (346 mg, 1.76 mmol)was diluted with (THF) 2 mL, methanol (2 mL) and 4 drops of sulfuricacid. The reaction was heated at 55° C. and stirred for 12 hours. Thereaction was cooled to ambient temperature, diluted with ethyl acetateand saturated sodium bicarbonate. The layers were separated and theorganic layer was dried over MgSO₄, filtered and concentrated to yieldthe title compound (366 mg, 98.7% yield).

Step D: Preparation of methyl6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate: Methyl7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (336 mg, 1.60 mmol) wasdiluted with DMF (5 mL) followed by the addition of N-bromosuccinimide(313 mg, 1.76 mmol). The reaction was heated at 50° C. and stirred for2.5 hours. The reaction was cooled, diluted with ethyl acetate andwashed with water, saturated sodium bicarbonate, water, and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated. Thematerial was purified using a Biotage 40M cartridge, gradient 5% ethylacetate/hexane to 50% to yield the title compound (415 mg, 89.8% yield).

Step E: Preparation of methyl 6-cyano-7-fluorochroman-4-carboxylate:Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg,1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by theaddition of Cu(I) CN (643 mg, 7.18 mmol). The reaction was bubbled withargon for 20 minutes, then heated at 160° C. under a slight argon bubblefor 6 hours. The reaction was cooled to ambient temperature and loadeddirectly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanesto 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).

Step F: Preparation of methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate:Methyl 6-cyano-7-fluorochroman-4-carboxylate (50 mg, 0.21 mmol) wasdiluted with 1-methyl-2-pyrrolidinone (2 mL) followed by the addition ofK₂CO₃ (147 mg, 1.1 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide(59 mg, 0.21 mmol). The reaction was bubbled with argon for 10 minutesand then heated to 110° C. and stirred for 6 hours. After the reactionwas allowed to cool, it was loaded directly onto a Biotage 25 column andeluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yieldmethyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(50 mg, 48% yield). MS (ESI)=490.9 (M+1).

Step G: Preparation of7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid: Methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(100 mg, 0.204 mmol) was diluted with THF (1 mL) followed by theaddition of NaOH (0.204 mL, 1.02 mmol) and 500 μL of water and methanol.After stirring for 3 hours, the reaction was diluted with ethyl acetateand 2N HCl. The layers were separated and the organic layer was driedover MgSO₄, filtered and concentrated. The material was purified usingthe Horizon with a 25 cartridge and running a gradient 0.5%methanol/0.5% acetic acid/CH₂Cl₂ to 10% methanol/0.5% acetic acid/CH₂Cl₂to yield the title compound (21 mg, 21.6% yield) as a white solid. MS(ESI)=476.9 (M+1).

EXAMPLE 27-(4-(4-chlorophenylcarbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylicacid

Step A: Preparation of methyl6-cyano-7-fluoro-4-methylchroman-4-carboxylate: Methyl6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (from Example 3,Step E; 28 mg, 0.12 mmol) was diluted with acetonitrile (1 mL) followedby the addition of K₂CO₃ (49 mg, 0.36 mmol) and iodomethane (0.023 mL,0.36 mmol). The reaction was then heated at 60° C. for 1 hour, thencooled and NaH (8.6 mg, 0.36 mmol) was added. The reaction was deemedcomplete by LC. The reaction was loaded onto a Biotage 25 samplet andpurified running a gradient 5% ethyl acetate/hexane to 100% ethylacetate/hexane to yield the title compound (10 mg, 34% yield).

Step B: Preparation of methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylate:Methyl 6-cyano-7-fluoro-4-methylchroman-4-carboxylate (10 mg, 0.040mmol) was diluted with N-methylpyrrolidone (2 mL) followed by theaddition of K₂CO₃ (28 mg, 0.20 mmol) andN-(4-chlorophenethyl)-4-hydroxybenzamide (11 mg, 0.040 mmol). Thereaction was bubbled with argon for 10 minutes and then heated at 110°C. and stirred for 5 hours. The reaction was allowed to cool, loadeddirectly onto a 25 samplet and eluted on the horizon with 5% ethylacetate/hexanes to 100% ethyl acetate/hexanes to yield the titlecompound (12 mg, 59% yield). MS (ESI)=504.9 (M+1).

Step C: Preparation of7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylicacid: Methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylate(12 mg, 0.0238 mmol) was diluted with THF (500 μL) followed by theaddition of NaOH (0.0475 mL, 0.238 mmol) and 200 μL of water andmethanol. After stirring for 3 hours, the reaction was diluted withethyl acetate and 2N HCl. The layers were separated and the organiclayer was dried over MgSO₄, filtered and concentrated. The material waspurified using the Horizon with a 25 cartridge and running a gradient0.5% methanol/0.5% acetic acid/CH₂Cl₂ to 10% methanol/0.5% aceticacid/CH₂Cl₂ to yield the title compound (4.0 mg, 34.3% yield) as a whitesolid. MS (ESI)=490.9 (M+1).

EXAMPLE 37-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylicacid

Step A: Preparation of 7-fluoro-2,2-dimethyl-2,3-dihydrochromen-4-one:To 1-(4-fluoro-2-hydroxyphenyl)ethanone (5.75 g, 37.3 mmol) andpropan-2-one (12 mL, 37.3 mmol) in benzene (50 mL) was added pyrrolidine(3.11 mL, 37.3 mmol) and the reaction heated at 80° C. for 3 hours. Thereaction was diluted with ethyl acetate (50 mL), washed with 1N HCl (50mL), brine (50 mL), dried over magnesium sulfate and concentrated. Theresidue was purified by silica gel chromatography, eluting with agradient of 5% ethyl acetate/hexanes to 50% ethyl acetate, to providethe title compound (5.12 g, 70.7% yield).

Step B: Preparation of7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylic acid: To7-fluoro-2,2-dimethyl-2,3-dihydrochromen-4-one (1.000 g, 5.149 mmol) wasadded trimethylsilyl cyanide (3.215 mL, 25.75 mmol) followed by aspatula tip of zinc iodide. The reaction was heated at 50° C. for 1hour. The reaction was cooled, diluted with ethyl acetate (40 mL) andwashed with saturated sodium bicarbonate (2×25 mL), brine (25 mL), driedover magnesium sulfate and concentrated. The product was dissolved in 5mL of acetic acid and 5 mL of HCl, and SnCl₂ dihydrate (4.648 g, 20.60mmol) was added. The reaction heated at reflux (130° C. oil bathtemperature) overnight. The reaction was cooled, diluted with ethylacetate (50 mL), washed with water (50 mL) and brine (50 mL), dried overmagnesium sulfate and concentrated. The residue was purified by silicagel chromatography over silica gel eluting with a gradient of 0.5%MeOH/CH₂Cl₂ containing 0.5% acetic acid to 10% MeOH/CH₂Cl₂ containing0.5% acetic acid to provide the title compound (0.280 g, 24.25% yield).

Step C: Preparation of methyl7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate: To7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylic acid (0.280g, 1.25 mmol) in CH₂Cl₂ (5 mL) and MeOH (1 mL) was added TMSCHN₂ (0.937mL, 1.87 mmol) dropwise. After the addition, the reaction wasconcentrated, loaded onto silica gel, and the product eluted using agradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes toprovide the title compound (0.225 g, 75.6% yield).

Step D: Preparation of methyl6-bromo-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate:Methyl 7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate (187mg, 0.785 mmol) was diluted with DMF (5 mL) followed by the addition ofN-bromosuccinimide (154 mg, 0.863 mmol). The reaction was heated at 50°C. for 2.5 hours. The reaction was cooled, diluted with ethyl acetateand washed with water, saturated sodium bicarbonate, water, and brine.The organic layer was dried over MgSO₄, filtered and concentrated. Thematerial was purified using a Biotage 40M cartridge, gradient 5% ethylacetate/hexane to 50% to yield the title compound (232 mg, 93.2% yield).

Step E: Preparation of methyl6-cyano-7-fluoro-2,2-dimethylchroman-4-carboxylate: methyl6-bromo-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylate (232mg, 0.732 mmol) was diluted with N-methylpyrrolidone (4 mL) followed bythe addition of Cu(I)CN (328 mg, 3.66 mmol). The reaction was bubbledwith Argon for 15 minutes and then heated at 160° C. The reaction wasstirred for 5 hours and then allowed to cool. The reaction was loadeddirectly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanesto 100% ethyl acetate to yield the title compound (120 mg, 62.3% yield).

Step F: Preparation of methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylate:Methyl 6-cyano-7-fluoro-2,2-dimethylchroman-4-carboxylate (19 mg, 0.072mmol) was diluted with N-methylpyrrolidone (2 mL) followed by theaddition of K₂CO₃ (25 mg, 0.18 mmol) andN-(4-chlorophenethyl)-4-hydroxybenzamide (20 mg, 0.072 mmol). Thereaction was bubbled with argon for 10 minutes and then heated at 110°C. for 6 hours. After cooling, the reaction mixture was loaded directlyonto a Biotage 25 column and eluted with 5% ethyl acetate/hexanes to100% ethyl acetate to yield the title compound (2.0 mg, 5.3% yield).

Step G: Preparation of7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylicacid: Methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylate(2.0 mg, 0.00385 mmol) was diluted with THF (500 μL) followed by theaddition of NaOH (0.00771 mL, 0.0385 mmol) and 200 μL of water andmethanol. After stirring for 3 hours, the reaction was diluted withethyl acetate and 2N HCl. The layers were separated and the organiclayer was dried over MgSO₄, filtered and concentrated. The material waspurified using a 0.5 mm preparative TLC plate, eluting with 5%methanol/0.5% acetic acid/CH₂Cl₂ to yield the title compound (0.6 mg,30.8% yield) as a white solid. MS (ESI)=504.9 (M+1).

EXAMPLE 46-Cyano-7-(4-(2,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of 6-cyano-7-fluorochroman-4-carboxylic acid: Methyl6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (45 mg, 0.19mmol) was diluted with THF (1 mL) followed the addition of NaOH (0.19mL, 0.96 mmol), 200 μL of water and methanol. After stirring for 3hours, the reaction was diluted with ethyl acetate and 2N HCl. Thelayers were separated and the organic layer was dried over MgSO₄,filtered and concentrated to yield the title compound (40 mg, 95%yield).

Step B: Preparation of7-(4-((2,4-dichlorophenethyl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid: 6-cyano-7-fluorochroman-4-carboxylic acid (40 mg, 0.18 mmol) wasdiluted with N-methylpyrrolidone (2 mL) followed by the addition ofK₂CO₃ (100 mg, 0.72 mmol) andN-(2,4-dichlorophenethyl)-4-hydroxybenzamide (56 mg, 0.18 mmol). Thereaction was bubbled with argon for 10 minutes and then heated at 140°C. After stirring for 5 hours, the reaction was loaded directly onto aBiotage 25 cartridge eluting with 0.5% acetic acid/0.5% methanol/CH₂Cl₂to 0.5% acetic acid/10% methanol/CH₂Cl₂ to yield the title compound (4.8mg, 5.2% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.57-8.59 (m, NH), 7.84 (d,J=8.7 Hz, 2H), 7.69 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.4 Hz,1H), 7.26 (dd, J=1.7, 8.0 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.40 (s, 1H),4.29-4.34 (m, 1H), 4.20-4.26 (m, 1H), 3.85 (t, J=5.1 Hz, 1H), 3.64 (q,J=6.1 Hz, 2H), 3.06 (t, J=7.0 Hz, 2H), 2.32-2.37 (m, 1H), 2.08-2.16 (m,1H).

EXAMPLE 5 6-Cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl7-(4-(tert-butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate: Methyl6-cyano-7-fluorochroman-4-carboxylate (from Example 3, Step E) (700 mg,2.98 mmol), tert-butyl 4-hydroxybenzoate (578 mg, 2.98 mmol) and K₂CO₃(494 mg, 3.57 mmol) were diluted with N-methylpyrrolidone (6 mL) andbubbled with argon for 10 minutes. The reaction was heated to 110° C.and stirred for 5 hours. The reaction was loaded directly onto a Biotage40M cartridge and eluted with 5% ethyl acetate/hexanes to 100% ethylacetate to yield the title compound (400 mg, 32.8% yield).

Step B: Preparation of4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid: Methyl7-(4-(tert-butoxycarbonyl)phenoxy)-6-cyanochroman-4-carboxylate (400 mg,0.977 mmol) was diluted with CH₂Cl₂ followed by the addition of TFA (1mL). After stirring for 2 hours, the reaction was concentrated to yieldthe title compound (240 mg, 69.5% yield).

Step C: Preparation of methyl 6-cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (13 mg,0.0368 mmol), HBTU (16.7 mg, 0.0442 mmol) were diluted withN-methylpyrrolidone (1 mL) followed by the addition of2-phenylethanamine (0.00647 mL, 0.0515 mmol), N,N-diisopropylethylamine(0.0160 mL, 0.0920 mmol) and DMAP (1.35 mg, 0.0110 mmol). After stirringfor 3 hours, the reaction was loaded directly onto a Biotage 12icartridge eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate toyield the title compound (16.1 mg, 95.9% yield).

Step D: Preparation of 6-cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Methyl6-cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (16.1 mg,0.0353 mmol) was diluted with THF (500 μL) followed by the addition ofNaOH (0.0705 mL, 0.353 mmol) and water (100 μL) and methanol (100 μL).After stirring for 3 hours, the reaction was diluted with ethyl acetateand 2N HCl. The layers were separated and the organic layer was driedover MgSO₄, filtered and concentrated to yield the title compound (12.0mg, 76.9% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.85 (d, 2H), 7.66 (s, 1H),7.20-7.30 (m, 5H), 7.15 (d, 2H), 6.40 (s, 1H), 4.20-4.35 (m, 2H), 3.85(bt, 1H), 3.58 (t, 2H), 2.92 (t, 2H), 2.3-2.4 (m, 1H), 2.1-2.2 (m, 1H).

EXAMPLE 66-Cyano-7-(4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of7-(4((2,3-dihydro-1H-inden-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate:4-(6-Cyano-4-(methoxycarbonyl) chroman-7-yloxy)benzoic acid (fromExample 7, Step B) (12 mg, 0.034 mmol), HBTU (15 mg, 0.041 mmol) werediluted with N-methylpyrrolidone (1 mL) followed by the addition of2-aminoindan (4.5 mg, 0.034 mmol), N,N-diisopropylethylamine (0.015 mL,0.085 mmol) and DMAP (1.2 mg, 0.010 mmol). After stirring for 3 hours,the reaction was loaded directly onto a Biotage 12i cartridge elutingwith 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the titlecompound (12 mg, 75% yield).

Step B: Preparation of7-(4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid: Methyl7-(4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate(12 mg, 0.026 mmol) was diluted with THF (500 μL) followed by theaddition of NaOH (1.0 mg, 0.026 mmol), water (200 μL) and methanol (200μL). After stirring for 2 hours, the reaction was diluted with 2N HCland ethyl acetate. The layers were separated and the organic layer wasdried over MgSO₄, filtered and concentrated to yield the title compound(10 mg, 86% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.90 (d, 2H), 7.64 (s,1H), 7.15-7.22 (m, 4H), 7.15 (d, 2H), 6.41 (s, 1H) 4.20-4.35 (m, 3H),3.82 (bt, 1H), 3.3-3.4 (m, 2H), 2.95-3.05 (m, 2H), 2.35-2.40 (m, 1H),2.10-2.15 (m, 1H).

EXAMPLE 77-(4-(4-Chlorobenzyloxycarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Step A: Preparation of methyl7-(4-((4-chlorobenzyloxy)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate:4-(6-cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)benzoicacid (from Example 7, Step B) (17 mg, 0.0481 mmol) was diluted withCH₂Cl₂ (1 mL) followed by the addition of oxalyl chloride in CH₂Cl₂ (2Min CH₂Cl₂) (0.0289 mL, 0.0577 mmol) and 1 drop of DMF. This was stirredfor 20 minutes followed by the addition ofO-(4-chlorobenzyl)hydroxylamine (15.2 mg, 0.0962 mmol) andN,N-diisopropylethylamine (0.0335 mL, 0.192 mmol). After stirring for 30minutes the reaction was loaded directly onto a Biotage 12i eluting withhexane:ethyl acetate (1:1) to yield the title compound (5 mg, 21.1%yield).

Step B: Preparation of7-(4-((4-chlorobenzyloxy)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid: Methyl 7-(4-((4-chlorobenzyloxy)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (5 mg,0.0101 mmol) was diluted with THF (500 μL) followed by the addition ofNaOH (0.0203 mL, 0.101 mmol), water (200 μL) and methanol (200 μL).After stirring for 2 hours, the reaction was diluted with 2N HCl andethyl acetate. The layers were separated and the organic layer was driedover MgSO₄, filtered and concentrated to yield the title compound (4.0mg, 82.3% yield). ¹H NMR (400 MHz, CD₃OD) δ 7.80 (d, 2H), 7.70 (s, 1H),7.48 (d, 2H), 7.40 (d, 2H), 7.15 (d, 2H), 6.41 (s, 1H), 4.95 (s, 2H),4.2-4.35 (m, 2H), 3.82 (bt, 1H), 2.35-2.40 (m, 1H), 2.10-2.15 (m, 1H).

EXAMPLE 86-Cyano-7-(4-(3,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl7-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate:4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)benzoicacid (17 mg, 0.0481 mmol) was diluted with CH₂Cl₂ (1 mL) followed by theaddition of oxalyl chloride in CH₂Cl₂ (2M in CH₂Cl₂) (0.0289 mL, 0.0577mmol) and 1 drop of DMF. The reaction was stirred for 20 minutes, andthen 3,4-dichlorobenzenamine (15.6 mg, 0.0962 mmol) andN,N-diisopropylethylamine (0.0210 mL, 0.120 mmol) were added. Afterstirring for 30 minutes the reaction was loaded directly onto a Biotage12i eluting with hexane:ethyl acetate (1:1) to yield the title compound(17 mg, 71.0% yield) as a clear oil.

Step B: Preparation of7-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid: Methyl 7-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (17 mg,0.034 mmol) was diluted with THF (500 μL) followed by the addition ofNaOH (0.041 mL, 0.21 mmol), water (200 μL) and methanol (200 μL). Afterstirring for 2 hours, the reaction was diluted with 2N HCl and ethylacetate. The layers were separated and the organic layer was dried overMgSO₄, filtered and concentrated to yield the title compound (10 mg, 61%yield). ¹H NMR (400 MHz, CD₃OD) δ 8.1 (d, 1H), 8.0 (d, 2H), 7.70 (s,1H), 7.62 (dd, 1H), 7.48 (d, 1H), 7.20 (d, 2H), 6.41 (s, 1H), 4.2-4.35(m, 2H), 3.82 (bt, 1H), 2.35-2.40 (m, 1H), 2.10-2.15 (m, 1H).

EXAMPLE 96-Chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-nitrophenoxy)chroman-4-carboxylicacid

Step A: Preparation of 4-chloro-N-(4-chlorophenethyl)-3-nitrobenzamide:2-(4-chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40mL) followed by the addition of DIEA (2.9 ml, 16 mmol) and4-chloro-3-nitrobenzoyl chloride (3.0 g, 14 mmol) dropwise in 10 mL ofDCM. After stirring for 30 minutes, the reaction was loaded onto silicagel and eluted with hexanes/ethyl acetate (2/1) to yieldN-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (4.0 g, 86% yield) as awhite solid.

Step B: Preparation of methyl6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-nitrophenoxy)chroman-4-carboxylate:Methyl 6-chloro-7-hydroxychroman-4-carboxylate (100 mg, 0.412 mmol)(Preparation 4, substituting methanol for ethanol in Step C) was dilutedwith DMSO (1 mL) followed by the addition of K₂CO₃ (68.3 mg, 0.495 mmol)and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (140 mg, 0.412mmol). The reaction was heated to 62° C. and stirred for 3 hours. Thereaction was cooled, loaded directly onto silica gel and eluted with 5%ethyl acetate/hexanes to 100% ethyl acetate to yield methyl7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate(60 mg, 26.7% yield).

Step C: Preparation of6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-nitrophenoxy)chroman-4-carboxylicacid: To a stirred solution of methyl7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate(5 mg, 0.00917 mmol) in THF (200 uL) was added NaOH (0.0183 ml, 0.0917mmol) followed by water and methanol (100 uL each). After stirring for 2hours, the reaction was diluted with ethyl acetate and 2N HCl. Thelayers were separated and the organic layer was dried over MgSO₄,filtered and concentrated to yield7-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylicacid (1.8 mg, 37.0% yield). LCMS (apci/pos)=533.0 (M+H).

EXAMPLE 106-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of ethyl6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (100 g, 265.40 mmol) was dissolved in drydichloromethane (750 ml) and few drops of DMF. Oxalyl Chloride (24.310ml, 278.67 mmol) was slowly added to the mixture under nitrogen streamover a period of 0.5 hours at ambient temperature. Gas evolution wasobserved. The mixture was stirred for 5 hours at ambient temperature andcooled in an ice bath. 2-(4-Chlorophenyl)ethanamine (40.602 ml, 291.94mmol) and diisopropylethylamine (55.624 ml, 318.48 mmol) were added. Themixture was warmed to ambient temperature and stirred for 16 hours. Thecrude mixture was transferred to a separatory funnel and washed with 1NHCl, water, and brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The resulting crude solid wasfurther dried under high vacuum to provide 143.5 g of a pink solid. Thissolid was recrystallized from hot EtOAc/hexanes to provide 130.0 g ofthe title compound as a light purple solid.

Step B: Preparation of6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Ethyl6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(128.8 g, 250.4 mmol) was dissolved in EtOH (250 mL) and THF (500 mL).NaOH (6N) (62.60 ml, 375.6 mmol) was added and the mixture was stirredat ambient temperature for 1.5 hours. The mixture was transferred to a 2L separatory funnel and 1N HCl (500.8 ml, 500.8 mmol) was added to themixture. Additional EtOAc (250 ml) was added and the layers wereseparated. The organic layer was washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The resulting crude solid was recrystallized from THF and hexanes toprovide 122.0 g of the title compound as a faint pink solid (yield95.0%). ¹H NMR analysis showed that the solid contained THF. The THFcontent was 27 mol % (5.2% weight) and the desired product content byweight was 94.8%. MS (apci) m/z=486.1 (M+H).

EXAMPLE 11 Separation of enantiomers of6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Separation of enantiomers of6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: 6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (Example 10; 140 g) was dissolved in methanol(50 mg/mL). The material was resolved via supercritical fluidchromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting with30% methanol/carbon dioxide at 100 bar, using 3 mL injections and a flowrate of 100 mL/min. Collection of fractions containing peak 2 andremoval of volatiles provided the more potent DP2 binding enantiomer,Enantiomer 2 of6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (65 g, 46% yield). MS (apci) m/z=486.1 (M+H).

EXAMPLE 12 Sodium6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate: To a stirred solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (75 mg, 0.20 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (84 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL)at ambient temperature was added phenethylamine (28 μL, 0.22 mmol) andN,N-diisopropylethylamine (105 μL, 0.60 mmol). The resulting yellowsolution was stirred at ambient temperature for 1 hour. The reactionmixture was diluted with water (10 mL) and extracted with ethyl acetate(10 mL). The organic layer was washed with brine (5 mL), then dried oversodium sulfate and concentrated to afford ethyl6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as anoff-white solid (89 mg, 93% yield).

Step B: Preparation of sodium 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate: To a stirred solution of ethyl6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (88 mg,0.18 mmol) in a mixture of tetrahydrofuran (0.6 mL) and ethanol (0.3 mL)at ambient temperature was added 1M sodium hydroxide (0.73 mL, 0.73mmol). The resulting slightly cloudy mixture was vigorously stirred atambient temperature for 1 hour. The reaction mixture was partitionedbetween ethyl acetate (10 mL) and 1M hydrochloric acid (5 mL). Theorganic layer was washed with brine (5 mL), then dried over sodiumsulfate and concentrated to afford the carboxylic acid as a colorlessoil (71 mg, 86% yield). To convert to the sodium salt, the oil wasdissolved in methanol (1 mL) and treated with a 25% (w/v) solution ofsodium methoxide in methanol (0.036 mL, 0.16 mmol). The resultingsolution was concentrated, and the residue was concentrated twice fromether to afford sodium6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as anoff-white glass (70 mg, 86% yield). MS (apci) m/z=452.1 (M+2H—Na).

EXAMPLE 13 Sodium6-chloro-7-(4-(4-phenylbutylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 12, substituting4-phenylbutylamine for phenethylamine. MS (apci) m/z=480.1 (M+2H—Na).

EXAMPLE 14 Sodium6-chloro-7-(4-(4-(3-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of(3-(1,3-dioxoisoindolin-2-yl)propyl)triphenyl-phosphonium bromide: Asolution of N-(3-bromopropyl)phthalimide (25.0 g, 93.2 mmol) andtriphenylphosphine (24.5 g, 93.2 mmol) in toluene (200 mL) was stirredand heated to reflux for 15 hours. The reaction mixture was cooled toambient temperature and the resulting precipitate was collected byfiltration, washed with toluene, and dried under vacuum to afford(3-(1,3-dioxoisoindolin-2-yl)propyl)triphenylphosphonium bromide as awhite powder (17.9 g, 36% yield).

Step B: Preparation of(Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione: To a stirredsuspension of (3-(1,3-dioxoisoindolin-2-yl)propyl)triphenylphosphoniumbromide (17.6 g, 33.2 mmol) in tetrahydrofuran (170 mL) at ambienttemperature was added 3-chlorobenzaldehyde (3.76 mL, 33.2 mmol), and theresulting mixture was cooled with a dry-ice acetone bath to −75° C.Solid potassium t-butoxide (3.72 g, 33.2 mmol) was added, and stirringwas continued in the bath for an additional 20 minutes; the temperaturewas −80° C. The cooling bath was removed, and when the internaltemperature reached −30° C., the flask was placed in a water-ice bath.The temperature eventually settled at 10° C. and was maintained for 2hours. The reaction mixture was poured into a separatory funnelcontaining water (250 mL), and this was extracted with ethyl acetate(250 mL). The organic layer was dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel,eluting with 90/10 hexanes/ethyl acetate, to afford(Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione as a whitesolid (8.46 g, 82% yield).

Step C: Preparation of (Z)-4-(3-chlorophenyl)but-3-en-1-amine: To astirred suspension of(Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione (8.4 g, 27mmol) in ethanol (100 mL) at ambient temperature was added hydrazinemonohydrate (65%, 2.6 mL, 54 mmol). The resulting mixture was stirredand heated to reflux, and a yellow solution formed upon attainingreflux. About 10 minutes after reflux began, a precipitate formed in thereaction mixture. After a total of 35 minutes at reflux, the precipitatenearly filled the flask, and the heat was removed. On reaching ambienttemperature, the reaction mixture formed a solid mass. The mass wasdissolved by adding of 2M sodium hydroxide (100 mL). The resultingsolution was concentrated to remove most of the ethanol. The remainingcloudy mixture was extracted with ethyl acetate (100 mL). The aqueouslayer turned into a gel and the organic layer was decanted away. Theorganic layer was washed with water (50 mL), then dried over sodiumsulfate and concentrated to afford(Z)-4-(3-chlorophenyl)but-3-en-1-amine as a light brown oil (4.66 g,95%).

Step D: Preparation of 4-(3-chlorophenyl)butan-1-amine: To a solution of(Z)-4-(3-chlorophenyl)but-3-en-1-amine (1.80 g, 9.91 mmol) in methanol(30 mL) was added platinum(IV) oxide (0.18 g, 0.79 mmol), and to theresulting stirred mixture at ambient temperature was fitted a balloon ofhydrogen. The flask was purged and refilled five times with hydrogen,and the resulting mixture was stirred at ambient temperature under aballoon of hydrogen for 1 hour. The catalyst was removed by filtrationthrough a glass microfibre filter, and the filtrate was concentrated toafford 4-(3-chlorophenyl)butan-1-amine as a light yellow oil (1.78 g,98% yield).

Step E: Preparation of sodium 6-chloro-7-(4-(4-(3-chlorophenol)butylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to themethod of Example 12, substituting 4-(3-chlorophenyl)butan-1-amine forphenethylamine. MS (apci) m/z=514.1 (M+2H—Na).

EXAMPLE 15 Sodium6-chloro-7-(4-(4-(4-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 4-(4-chlorophenyl)butanamide: To a stirredsolution of 4-(4-chlorophenyl)butanoic acid (3.97 g, 20.0 mmol) and1-hydroxybenzotriazole hydrate (3.37 g, 22.0 mmol) inN,N-dimethylformamide (40 mL) at ambient temperature was added solid1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.21 g, 22mmol). The resulting mixture was stirred at ambient temperature for 25minutes, and a solution of ammonia in methanol (7M, 14.3 mL, 100 mmol)was added. After stirring at ambient temperature for a further 15minutes, the reaction mixture was diluted with water (400 mL) andextracted with chloroform (100 mL). The organic layer was dried oversodium sulfate and concentrated. The residual oil was triturated withhexane to afford a solid, which was collected by filtration, washed withhexane, and dried under vacuum to afford 4-(4-chlorophenyl)butanamide asan off-white powder (2.40 g, 61% yield).

Step B: Preparation of 4-(4-chlorophenyl)butan-1-amine: To a stirredsuspension of lithium aluminum hydride (1.84 g, 48.6 mmol) in diethylether (50 mL) at ambient temperature was added a solution of4-(4-chlorophenyl)butanamide in tetrahydrofuran (25 mL), dropwise over 8minutes. Stirring was continued at ambient temperature for a further 4hours. The reaction mixture was carefully quenched by sequential slowaddition of water (2 mL), 10M sodium hydroxide (0.75 mL), and water (7mL). After stirring the mixture for 20 minutes, it was extracted withdiethyl ether (50 mL). The organic layer was dried over sodium sulfateand concentrated to afford 4-(4-chlorophenyl)butan-1-amine as a lightyellow oil (1.36 g, 61%).

Step C: Preparation of sodium 6-chloro-7-(4-(4-(4-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to themethod of Example 12, substituting 4-(4-chlorophenyl)butan-1-amine forphenethylamine. MS (apci) m/z=514.1 (M+2H—Na).

EXAMPLE 16 Sodium(Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of (Z)-4-(2-chlorophenyl)but-3-en-1-amine: Preparedaccording to Steps A through C of Example 14, substituting2-chlorobenzaldehyde for 3-chlorobenzaldehyde.

Step B: Preparation of Sodium(Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Example 12, substituting(Z)-4-(2-chlorophenyl)but-3-en-1-amine for phenethylamine. MS (apci)m/z=512.0 (M+2H—Na).

EXAMPLE 17 Sodium6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate

To a solution of sodium(Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate(0.16 g, 0.31 mmol) in methanol (2 mL) was added platinum(IV) oxide(0.018 g, 0.079 mmol), and to the resulting stirred mixture at ambienttemperature was fitted a balloon of hydrogen. The flask was purged andrefilled five times with hydrogen, and the resulting mixture was stirredat ambient temperature under a balloon of hydrogen for 30 minutes, bywhich time the catalyst had clumped up. The methanol supernatant wasdecanted away from the catalyst with a pipet and concentrated, and theresidue concentrated from diethyl ether to afford sodium6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylateas a white glass (142 mg, 87% yield). MS (apci) m/z=514.1 (M+2H—Na).

EXAMPLE 18 Sodium(Z)-6-chloro-7-(4-(4-(2,4-dichlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of (Z)-4-(2,4-dichlorophenyl)but-3-en-1-amine:Prepared according to Steps A through C of Example 14, substituting2,4-dichlorobenzaldehyde for 3-chlorobenzaldehyde.

Step B: Preparation of sodium(Z)-6-chloro-7-(4-(4-(2,4-dichlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Example 12, substituting(Z)-4-(2,4-dichlorophenyl)but-3-en-1-amine for phenethylamine. MS (apci)m/z=545.9 (M+2H—Na).

EXAMPLE 19 Sodium6-chloro-7-(4-(4-(2,4-dichlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 17, substituting sodium(Z)-6-chloro-7-(4-(4-(2,4-dichlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylatefor sodium(Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate.MS (apci) m/z=548.1 (M+2H—Na).

EXAMPLE 20 Sodium6-chloro-7-(4-(2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 12, substituting2-methylphenethylamine for phenethylamine. MS (apci) m/z=466.0(M+2H—Na).

EXAMPLE 21 Sodium6-chloro-7-(4-(2,4-dimethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 12, substituting2,4-dimethylphenethylamine for phenethylamine. MS (apci) m/z=480.0(M+2H—Na).

EXAMPLE 22 Sodium6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a stirred solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (75 mg, 0.20 mmol) and 1-hydroxybenzotriazole hydrate(34 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambienttemperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimidehydrochloride (47 mg, 0.24 mmol). The resulting solution was stirred atambient temperature for 20 minutes, and 4-methylphenethylamine (30 mg,0.23 mmol) was added. After stirring was at ambient temperature for afurther 30 minutes, the mixture was diluted with water (10 mL) andextracted with ethyl acetate (5 mL). The organic layer was washed withbrine (2 mL), then dried over sodium sulfate and concentrated to affordethyl6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylateas a colorless oil (96 mg, 96% yield).

Step B: Preparation of sodium6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Step B of Example 12, substitutingafford ethyl6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylatefor ethyl6-chloro-7-(4-z(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate. MS(apci) m/z=494.1 (M+2H—Na).

EXAMPLE 23 Sodium7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Step A: Preparation of ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:Prepared according to Example 22, step A, substituting4-bromophenethylamine for 4-methylphenethylamine (2.70 g, 95% yield).

Step B: Preparation of sodium7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate.Prepared according to the method of Step B of Example 12, substitutingethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate. MS(apci) m/z=530.0 (M+2H—Na).

EXAMPLE 24 Sodium6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a stirred suspension of ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(0.56 g, 1.0 mmol) in toluene (6 mL) at ambient temperature was addedsuccessively water (0.3 mL), potassium phosphate (0.64 g, 3.0 mmol),tricyclohexylphosphine (0.11 g, 0.40 mmol), and cyclopropylboronic acid(0.17 g, 2.0 mmol). The resulting mixture was stirred and a balloon ofnitrogen with a three-way purge valve was attached, and the flask wasevacuated and refilled five times with nitrogen. Palladium(II) acetate(0.045 g, 0.20 mmol) was added, and again the flask was evacuated andrefilled five times with nitrogen. The mixture was stirred in an oilbath set to 100° C. under the nitrogen balloon for 3 hours. The mixturewas cooled to ambient temperature and diluted with ethyl acetate (25 mL)and water (15 mL). The organic layer was dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel,eluting with 70/30 hexanes/ethyl acetate, to afford ethyl6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylateas a white solid (0.24 g, 46% yield).

Step B: Preparation of sodium 6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate. Prepared according to themethod of Step B of Example 12, substituting ethyl6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylatefor ethyl6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate. MS(apci) m/z=492.0 (M+2H—Na).

EXAMPLE 25 Sodium6-chloro-7-(4-(2-cyclopropylethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 22, substituting2-cyclopropylethylamine for 4-methylphenethylamine. MS (apci) m/z=416.0(M+2H—Na).

EXAMPLE 26 Sodium6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a stirred suspension of ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(0.56 g, 1.0 mmol) and 2-chlorophenylboronic acid (0.17 g, 1.1 mmol) ina mixture of 1,2-dimethoxyethane (4 mL) and methanol (2 mL) was addedcesium fluoride (0.30 g, 2.0 mmol), followed bytetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol). Theresulting mixture was stirred in an oil bath set to 80° C. for 1 hour.The mixture was cooled to ambient temperature and diluted with water (20mL) and extracted with dichloromethane (2×20 mL). The organic layerswere combined and dried over sodium sulfate, then concentrated. Theresidue was purified by chromatography on silica gel, eluting with 80/20hexanes/ethyl acetate, to afford ethyl6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylateas a light brown oil (0.35 g, 59% yield).

Step B. Preparation of sodium6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Step B of Example 12, substitutingethyl6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylatefor ethyl6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate. MS(apci) m/z=562.0 (M+2H—Na).

EXAMPLE 27 Sodium6-chloro-7-(4-(4-chloro-2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 4-chloro-2-methyl-1-(2-nitrovinyl)benzene: Amixture of 4-chloro-2-methylbenzaldehyde (1.56 g, 10.1 mmol),methylamine hydrochloride (0.44 g, 6.5 mmol), and sodium acetate (0.53g, 6.5 mmol) in nitromethane (4 mL) was vigorously stirred at ambienttemperature for 24 hours. The reaction mixture was diluted with water(20 mL) and dichloromethane (40 mL). The organic layer was dried oversodium sulfate and evaporated to afford4-chloro-2-methyl-1-(2-nitrovinyl)benzene as a light brown solid (1.87g, 94% yield).

Step B: Preparation of 2-(4-chloro-2-methylphenyl)ethanamine: A solutionof 4-chloro-2-methyl-1-(2-nitrovinyl)benzene (1.83 g, 9.26 mmol) intetrahydrofuran (40 mL) was cooled to 0° C. in an ice bath, and a 1Msolution of lithium aluminum hydride in tetrahydrofuran (37 mL, 37 mmol)was added, dropwise over 10 minutes. The resulting mixture was stirredin the ice bath for 2 hours 30 minutes, then quenched in the followingmanner: water (1.5 mL) was added dropwise, and after stirring for 5minutes, 1M sodium hydroxide (1.5 mL) was added. After stirring for afurther 15 minutes, water (5 mL) was added, and the resulting mixturewas stirred at ambient temperature for 15 minutes, then filtered througha medium porosity sintered glass funnel. The collected precipitate waswashed with ethyl acetate (60 mL). The combined filtrate and wash wasdried over sodium sulfate and concentrated to afford2-(4-chloro-2-methylphenyl)ethanamine as a brown oil (1.17 g, 75%yield).

Step C: Preparation of sodium6-chloro-7-(4-(4-chloro-2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Example 22, substituting2-(4-chloro-2-methylphenyl)ethanamine for 4-methylphenethylamine. MS(apci) m/z=500.1 (M+2H—Na).

EXAMPLE 28 Sodium7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Step A: Preparation of 4-bromo-2-chloro-1-(dibromomethyl)benzene: To astirred solution of 4-bromo-2-chlorotoluene (6.50 mL, 48.7 mmol) andbenzoyl peroxide (0.51 g, 2.1 mmol) in carbon tetrachloride (80 mL) wasadded N-bromosuccinimide (43.3 g, 243 mmol), and the resulting mixturewas stirred and heated to reflux for 15 hours. The mixture was cooled toambient temperature and the insoluble material was removed byfiltration, and washed twice with carbon tetrachloride. The filtrate andwashings were combined and concentrated. The residue was purified bychromatography on silica gel, eluting with hexanes, to afford4-bromo-2-chloro-1-(dibromomethyl)benzene as a colorless liquid (17.7 g,100% yield).

Step B: Preparation of 4-bromo-2-chlorobenzaldehyde: A solution of4-bromo-2-chloro-1-(dibromomethyl)benzene (17.7 g, 48.7 mmol) in ethanol(25 mL) was stirred and heated to reflux, and a solution of silver(I)nitrate (77.4 g, 456 mmol) in water (55 mL) was added dropwise over 20minutes. The mixture turned yellow and a precipitate of silver bromideformed immediately upon addition. Following completion of addition, themixture was stirred at reflux for an additional hour. After cooling toambient temperature, the mixture was diluted with water (200 mL) andfiltered to remove insoluble material. The filtrate was extracted withchloroform (200 mL), and the insoluble material was washed withchloroform (2×200 mL). The three chloroform layers were combined andwashed with water (250 mL), dried over sodium sulfate and concentratedto afford 4-bromo-2-chlorobenzaldehyde (10.6 g, 99% yield).

Step C: Preparation of 4-bromo-2-chloro-1-(2-nitrovinyl)benzene.Prepared according to the method of Step A of Example 27, substituting4-bromo-2-chlorobenzaldehyde for 4-chloro-2-methylbenzaldehyde.

Step D: Preparation of 2-(4-bromo-2-chlorophenyl)ethanamine: To astirred suspension of lithium borohydride (0.29 g, 13 mmol) intetrahydrofuran (20 mL) at ambient temperature was addedchlorotrimethylsilane (3.4 mL, 27 mmol), dropwise over 2 minutes. Afterstirring at ambient temperature for 20 minutes, argon gas was bubbledthrough the mixture for 2 minutes to remove the remainingtrimethylsilane that had formed. A solution of4-bromo-2-chloro-1-(2-nitrovinyl)benzene (0.88 g, 3.4 mmol) intetrahydrofuran (15 mL) was added dropwise over 4 minutes with stirringat ambient temperature. The resulting mixture was stirred and heated toreflux for 1 hour. The mixture was cooled in an ice bath and carefullyquenched with methanol (20 mL). The solvent was evaporated, and theresidue was partitioned between 20% potassium hydroxide (40 mL) anddichloromethane (20 mL). The organic layer was dried over sodium sulfateand concentrated to afford 2-(4-bromo-2-chlorophenyl)ethanamine as alight yellow oil (0.75 g, 95% yield).

Step E: Preparation of ethyl7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:To a stirred solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (1.15 g. 3.05 mmol), 1-hydroxybenzotriazole hydrate(0.51 g, 3.4 mmol) and 2-(4-bromo-2-chlorophenyl)ethanamine (0.75 g, 3.2mmol) in N,N-dimethylformamide (10 mL) at ambient temperature was addedsolid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g,3.7 mmol). The resulting solution was stirred at ambient temperature for17 hours, then diluted with water (100 mL) and extracted with ethylacetate (100 mL). Addition of 1M hydrochloric acid (20 mL) enabled layerseparation. The organic layer was dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel,eluting with 75/25 hexanes/ethyl acetate, to afford ethyl7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylateas an off-white solid (1.10 g, 60% yield).

Step F: Preparation of sodium7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:Prepared according to Step B of Example 12, substituting ethyl7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate. MS(apci) m/z=564.0 (M+2H—Na).

EXAMPLE 29 Sodium6-chloro-7-(4-(2-(2′,3-dichlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 26, substituting ethyl7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=596.0 (M+2H—Na).

EXAMPLE 30 Sodium6-chloro-7-(4-(2-chloro-4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 24, substituting ethyl7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=526.0 (M+2H—Na).

EXAMPLE 31 Sodium6-chloro-7-(4-(2-(3-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 26, substituting ethyl7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate,and substituting phenylboronic acid for 2-chlorophenylboronic acid. MS(apci) m/z=562.1 (M+2H—Na).

EXAMPLE 32 Sodium7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Prepared according to the method of Example 28, substituting2-bromo-4-chlorotoluene for 4-bromo-2-chlorotoluene. MS (apci) m/z=564.0(M+2H—Na).

EXAMPLE 33 Sodium6-chloro-7-(4-(2-(2′,5-dichlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 26, substituting ethyl7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=596.1 (M+2H—Na).

EXAMPLE 34 Sodium6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 24, substituting ethyl7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=525.9 (M+2H—Na).

EXAMPLE 35 Sodium7-(4-(4-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Step A: Preparation of 4-bromo-2-methoxybenzaldehyde: To a stirredsolution of 4-bromo-2-fluorobenzaldehyde (96%, 3.38 g, 16.0 mmol) inmethanol (35 mL) at ambient temperature was added a 25 wt % solution ofsodium methoxide in methanol (4.02 mL, 17.6 mmol), and the resultingsolution was stirred and heated to reflux for 2 hours. The solution wascooled to ambient temperature and concentrated, and the residue waspartitioned between dichloromethane (100 mL) and water (50 mL). Theorganic layer was dried over sodium sulfate and concentrated. Theresidue was purified by chromatography on silica gel, eluting with 95/5hexanes/ethyl acetate, to afford 4-bromo-2-methoxybenzaldehyde as awhite solid (2.13 g, 62% yield).

Step B: Preparation of sodium7-(4-(4-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:Prepared according to the method of Steps C through F of Example 28,substituting 4-bromo-2-methoxybenzaldehyde for4-chloro-2-methylbenzaldehyde. MS (apci) m/z=559.9 (M+2H—Na).

EXAMPLE 36 Sodium6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 24, substituting ethyl7-(4-(4-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylatefor ethyl7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=522.0 (M+2H—Na).

EXAMPLE 37 Sodium6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 2,4-dichloro-6-methoxybenzaldehyde: To a stirredsolution of 2,4-dichloro-6-hydroxybenzaldehyde (1.85 g, 9.69 mmol) inN,N-dimethylformamide (20 mL) at ambient temperature was added solidpotassium carbonate (1.47 g, 10.7 mmol), and the resulting yellowmixture was stirred at ambient temperature for 30 minutes. Iodomethane(2.42 mL, 38.7 mmol) was added, and the resulting mixture was stirred inan oil bath set to 50° C. for 30 minutes. The mixture was cooled toambient temperature and diluted with water (200 mL). After stirring for10 minutes, the precipitate that formed was collected by filtration,washed with water, and dried under vacuum to afford2,4-dichloro-6-methoxybenzaldehyde as an off-white powder (1.93 g, 97%yield).

Step B. Preparation of Sodium6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Steps C through F of Example 28,substituting 2,4-dichloro-6-methoxybenzaldehyde for4-chloro-2-methylbenzaldehyde. MS (apci) m/z=549.9 (M+2H—Na).

EXAMPLE 38 Sodium8-bromo-6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl8-bromo-6-chloro-7-hydroxychroman-4-carboxylate: To a stirred solutionof ethyl 6-chloro-7-hydroxychroman-4-carboxylate (5.14 g, 20.0 mmol) inglacial acetic acid (50 mL) at ambient temperature was added bromine(1.2 mL, 24 mmol), in six equal portions, waiting 30-60 seconds betweeneach addition for the bromine color to be discharged. Followingcompletion of addition, the solution was concentrated and the residueconcentrated from toluene, then partitioned between ethyl acetate (200mL) and 5% sodium bisulfite (100 mL). The organic was layer dried oversodium sulfate, then stirred with activated charcoal (2 g) at ambienttemperature for 20 minutes. The charcoal was removed by filtrationthrough a glass microfibre filter and the filtrate was concentrated toafford ethyl 8-bromo-6-chloro-7-hydroxychroman-4-carboxylate as a lightbrown oil (6.05 g, 90% yield).

Step B: Preparation of ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate:To a stirred solution of ethyl8-bromo-6-chloro-7-hydroxychroman-4-carboxylate (4.00 g, 11.9 mmol) andtert-butyl 4-fluoro-3-nitrobenzoate (3.16 g, 13.1 mmol) inN,N-dimethylformamide (66 mL) at ambient temperature was added solidpotassium carbonate (2.64 g, 19.1 mmol). The resulting mixture wasstirred in an oil bath set to 90° C. for 30 minutes. The mixture wascooled to ambient temperature and poured into a reparatory funnelcontaining water (600 mL). Chloroform (300 mL) was added, followed by 1Mhydrochloric acid (100 mL). The organic layer was dried over sodiumsulfate and concentrated. The residue was purified by chromatography onsilica gel, eluting with 90/10 hexanes/ethyl acetate to afford ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylateas a light yellow glass (4.33 g, 65% yield).

Step C: Preparation of ethyl7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-8-bromo-6-chlorochroman-4-carboxylate:To a stirred solution of ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate(2.00 g, 3.59 mmol) in tetrahydrofuran (15 mL) at ambient temperaturewas added zinc dust (4.70 g, 71.8 mmol), followed by saturated ammoniumchloride solution (7.5 mL). The resulting mixture was stirred at ambienttemperature for 1 hour. The mixture was filtered through a glassmicrofibre filter to remove the insoluble zinc solids, and the solidswere washed twice with tetrahydrofuran. The combined filtrate andwashings were concentrated to remove most of the tetrahydrofuran, andthe residue was partitioned between ethyl acetate (100 mL) and water (50mL). The organic layer was washed with brine (50 mL), then dried oversodium sulfate and concentrated to afford ethyl7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-8-bromo-6-chlorochroman-4-carboxylateas a light brown glass (1.61 g, 85% yield).

Step D: Preparation of ethyl8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate:N,N-dimethylformamide (20 mL) was heated in an oil bath set to 70° C.Isobutyl nitrite (0.90 mL, 7.6 mmol) was added, and to the resultingstirred solution at 68° C. was added a solution of ethyl7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-8-bromo-6-chlorochroman-4-carboxylate(1.6 g, 6.0 mmol) in N,N-dimethylformamide (6 mL), dropwise over 5minutes. The resulting solution was stirred at 70° C. for 30 minutes.The resulting red solution was cooled to ambient temperature andpartitioned between water (600 mL) and ethyl acetate (50 mL). Theorganic layer was washed with 1M hydrochloric acid (10 mL) and brine (10mL), then dried over sodium sulfate and concentrated. The residue waspurified by chromatography on silica gel, eluting with 95/5 to 85/15hexanes/ethyl acetate, to afford ethyl8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylateas an orange oil (0.27 g, 17% yield).

Step E: Preparation of4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid: To astirred solution of ethyl8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate(0.26 g, 0.51 mmol) in dichloromethane (5 mL) at ambient temperature wasadded trifluoroacetic acid (5 mL). The resulting solution was stirred atambient temperature for 30 minutes. The solution was concentrated andthe residual glassy solid was redissolved in ethyl acetate (2 mL).Hexanes (10 mL) were added, and after mixing for a few minutes, theproduct solidified. The mixture was concentrated to afford4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid as alight brown powder (0.23 g, 99% yield).

Step F: Preparation of Sodium8-bromo-6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Example 12, substituting4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid for4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid andsubstituting 2-(4-chlorophenyl)ethanamine for phenethylamine. MS (apci)m/z=564.0 (M+2H—Na).

EXAMPLE 39 Sodium7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6,8-dicyclopropylchroman-4-carboxylate

Step A: Preparation of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dicyclopropylchroman-4-carboxylate:To a stirred solution of ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate(Example 38, Step B; 0.56 g, 1.0 mmol) in xylenes (6 mL) was addedsuccessively water (0.3 mL), potassium phosphate (1.27 g, 6.0 mmol),tricyclohexylphosphine (0.11 g, 0.40 mmol), and cyclopropylboronic acid(0.34 g, 4.0 mmol). The resulting mixture was stirred and a balloon ofnitrogen with a three-way purge valve was attached, and the flask wasevacuated and refilled five times with nitrogen. Palladium(II) acetate(0.045 g, 0.20 mmol) was added, and again the flask was evacuated andrefilled five times with nitrogen. The mixture was stirred in an oilbath set to 140° C. under the nitrogen balloon for 2 hours. The mixturewas cooled to ambient temperature, and diluted with ethyl acetate (25mL) and water (15 mL). The organic layer was dried over sodium sulfateand concentrated. The residue was purified by chromatography on silicagel, eluting with 90/10 hexanes/ethyl acetate, to afford ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dicyclopropylchroman-4-carboxylateas a light yellow glass (0.24 g, 46%).

Step B: Preparation of sodium7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6,8-dicyclopropylchroman-4-carboxylate:Prepared according to the method of Steps C through F of Example 38,substituting ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dicyclopropylchroman-4-carboxylatefor ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=532.2 (M+2H—Na).

EXAMPLE 40 Sodium6,8-dicyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 39, substituting2-(2,4-dichlorophenyl)ethanamine for 2-(4-chlorophenyl)ethanamine. MS(apci) m/z=566.1 (M+2H—Na).

EXAMPLE 41 Sodium7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6-cyclopropylchroman-4-carboxylate

Step A: Preparation of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate:Prepared according to the method of Step B of Example 38, substitutingethyl 6-chloro-7-hydroxychroman-4-carboxylate for ethyl8-bromo-6-chloro-7-hydroxychroman-4-carboxylate.

Step B: Preparation of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-cyclopropylchroman-4-carboxylate:To a stirred solution of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate(1.38 g, 2.89 mmol) in toluene (15 mL) was added successively water(0.75 mL), potassium phosphate (3.06 g, 14.4 mmol),tricyclohexylphosphine (0.32 g, 1.16 mmol), and cyclopropylboronic acid(0.74 g, 8.7 mm3ol). The resulting mixture was stirred and a balloon ofnitrogen with a three-way purge valve was attached, and the flask wasevacuated and refilled five times with nitrogen. Palladium(II) acetate(0.13 g, 0.58 mmol) was added, and again the flask was evacuated andrefilled five times with nitrogen. The mixture was stirred in an oilbath set to 110° C. under the nitrogen balloon for 16 hours. The mixturewas cooled to ambient temperature, and diluted with ethyl acetate (100mL) and water (50 mL). The organic layer was dried over sodium sulfateand concentrated. The residue was purified by chromatography on silicagel, eluting with 95/5 hexanes/ethyl acetate, to afford ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-cyclopropylchroman-4-carboxylateas a yellow oil (0.39 g, 28%).

Step C: Preparation of Sodium7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6-cyclopropylchroman-4-carboxylate:Prepared according to the method of Steps C through F of Example 38,substituting ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-cyclopropylchroman-4-carboxylatefor ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate.MS (apci) m/z=492.1 (M+2H—Na).

EXAMPLE 42 Sodium6-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 41, substituting2-(2,4-dichlorophenyl)ethanamine for 2-(4-chlorophenyl)ethanamine. MS(apci) m/z=526.1 (M+2H—Na).

EXAMPLE 43 Sodium6-chloro-8-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chloro-8-cyclopropylchroman-4-carboxylate:To a stirred solution of ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate(0.59 g, 1.05 mmol) in toluene (6 mL) was added successively water (0.3mL), potassium phosphate (0.67 g, 3.2 mmol), tricyclohexylphosphine(0.12 g, 0.42 mmol), and cyclopropylboronic acid (0.18 g, 2.1 mmol). Theresulting mixture was stirred and a balloon of nitrogen with a three-waypurge valve was attached, and the flask was evacuated and refilled fivetimes with nitrogen. Palladium(II) acetate (0.047 g, 0.21 mmol) wasadded, and again the flask was evacuated and refilled five times withnitrogen. The mixture was stirred in an oil bath set to 100° C. underthe nitrogen balloon for 1.5 hours. The mixture was cooled to ambienttemperature, and diluted with ethyl acetate (25 mL) and water (15 mL).The organic layer was dried over sodium sulfate and concentrated. Theresidue was purified by chromatography on silica gel, eluting with 85/15hexanes/ethyl acetate, to afford ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chloro-8-cyclopropylchroman-4-carboxylateas a yellow oil (0.28 g, 51%).

Step B: Preparation of4-(6-chloro-8-cyclopropyl-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid: Prepared according to Steps C through E of Example 38,substituting ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chloro-8-cyclopropylchroman-4-carboxylatefor ethyl8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate.

Step C: Preparation of sodium6-chloro-8-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to Steps E and F of Example 28, substituting4-(6-chloro-8-cyclopropyl-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acidfor 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid, andsubstituting 2-(2,4-dichlorophenyl)ethanamine for2-(4-bromo-2-chlorophenyl)ethanamine. MS (apci) m/z=560.1 (M+2H—Na).

EXAMPLE 446-Cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of 4-(2-(tert-butoxycarbonylamino)ethyl)benzoicacid: To a solution of 4-(2-aminoethyl)benzoic acid hydrochloride (10.0g, 49.6 mmol) in a mixture of tert-butanol (liquefied, 7% water, 150 mL)and 1M sodium hydroxide (150 mL) at ambient temperature was addeddi-tert-butyl dicarbonate (13.0 g, 59.5 mmol). The resulting solutionwas stirred at ambient temperature for 16 hours. The reaction mixturewas transferred to a separatory funnel containing water (250 mL), andwas washed with hexanes (2×250 mL). The aqueous layer was acidified topH<2 with concentrated hydrochloric acid. The precipitate that formedwas allowed to stir for several minutes, collected by filtration, washedwith a small amount of water, and dried under vacuum to afford4-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid as a white powder(12.5 g, 95% yield).

Step B: Preparation of tert-butyl 4-(hydroxymethyl)phenethylcarbamate: A1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (100mL, 100 mmol) was added directly to solid(4-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid (12.4 g, 46.7 mmol).The resulting solution was stirred at ambient temperature for 1 hour,carefully quenched with water (250 mL), and extracted with ethyl acetate(500 mL). The organic layer was washed with saturated sodium bicarbonate(200 mL) and brine (100 mL), dried over sodium sulfate and concentratedto afford tert-butyl 4-(hydroxymethyl)phenethylcarbamate as a paleyellow oil (10.0 g, 85% yield).

Step C: Preparation of 4-(2-(tert-butoxycarbonylamino)ethyl)benzylmethanesulfonate: A solution of tert-butyl4-(hydroxymethyl)phenethylcarbamate (2.51 g, 9.99 mmol) andN,N-diisopropylethylamine (1.9 mL, 11 mmol) in tetrahydrofuran (50 mL)was stirred and cooled in an ice bath. Methanesulfonyl chloride (0.85mL, 11 mmol) was added in several portions, and stirring was continuedin the bath for 50 minutes. The reaction mixture was transferred to aseparatory funnel containing ethyl acetate (200 mL) and brine (200 mL).The organic layer was dried over sodium sulfate and concentrated toafford 4-(2-(tert-butoxycarbonylamino)ethyl)benzyl methanesulfonate as asoft white solid. (3.29 g, 100% yield).

Step D: Preparation of tert-butyl4-((dimethylamino)methyl)phenethylcarbamate: To a stirred suspension of4-(2-(tert-butoxycarbonylamino)ethyl)benzyl methanesulfonate (0.33 g,1.0 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) intetrahydrofuran (50 mL) was added a 2M solution of dimethylamine intetrahydrofuran (5.0 mL, 10 mmol). The resulting mixture was stirred inan oil bath set to 60° C. for 6 hours. The solution was cooled toambient temperature and concentrated. The residue was partitionedbetween ethyl acetate (20 mL) and water (10 mL). The organic layer wasdried over sodium sulfate and concentrated. The residue was purified bychromatography on silica gel, eluting with 99/1 to 98/2chloroform/(90/10 methanol/concentrated ammonium hydroxide), to affordtert-butyl 4-((dimethylamino)methyl)phenethylcarbamate as a colorlessoil (0.15 g, 54% yield).

Step E: Preparation of 2-(4-((dimethylamino)methyl)phenyl)ethanaminedihydrochloride: To a stirred solution of tert-butyl4-((dimethylamino)methyl)phenethylcarbamate (0.14 g, 0.50 mmol) indioxane (1 mL) at ambient temperature was added a 4M solution ofhydrogen chloride in dioxane (4 mL). The resulting solution was stirredat ambient temperature for 30 minutes, then concentrated to afford2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride as a whitesolid (0.12 g, 98% yield).

Step F: Preparation of methyl6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a stirred suspension of4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride(0.056 g, 0.31 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL,1.4 mmol). The resulting solution was stirred at ambient temperature for60 minutes, then partitioned between water (15 mL) and ethyl acetate (10mL). The organic layer was dried over sodium sulfate and concentrated.The residue was purified by chromatography on silica gel, eluting with90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), toafford methyl6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylateas a colorless film (0.083 g, 57% yield).

Step G: Preparation of6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a stirred solution of methyl6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(83 mg, 0.16 mmol) in methanol (1 mL) at ambient temperature was added a2M solution of sodium hydroxide (0.40 mL, 0.80 mmol). After stirring atambient temperature for 1 hour the solution was concentrated, and theresidual solid was redissolved in water (5 mL). The pH was adjusted to4.5 to precipitate the product, and chloroform (5 mL) was added. Afterstirring the multiphase mixture for a few minutes, the product separatedas a thick oil on the side of the flask. The chloroform/water mixturewas decanted away and the residue dried under vacuum to afford6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid as a light yellow glass (23 mg, 28% yield). MS (apci) m/z=500.1(M+H).

EXAMPLE 456-Cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid hydrochloride

Step A: Preparation of 7-nitro-1,2,3,4-tetrahydroisoquinolinehydrochloride: Concentrated sulfuric acid (70 mL) was cooled in anice-salt bath to 0° C. 1,2,3,4-Tetrahydroisoquinoline (96%, 19.6 g, 141mmol) was added dropwise in portions over 35 minutes, with thetemperature mostly staying below 20° C., but occasional brief excursionsas high as 40° C. The resulting mixture was again cooled in an ice-saltbath to 0° C. and solid potassium nitrate (15.7 g, 155 mmol) was addedin portions over 60 minutes, keeping the temperature mostly below 5° C.with occasional brief excursions as high as 7° C. Following completionof addition, the bath was removed and the resulting mixture was allowedto stir overnight at ambient temperature. The mixture was addedcarefully in small portions over 2 hours to concentrated ammoniumhydroxide (200 mL), cooled initially in an ice-salt bath to −2° C. Theresulting mixture was diluted with chloroform (400 mL) and the mixturestirred overnight at ambient temperature. Additional concentratedammonium hydroxide was added to bring the pH to about 11. The mixturewas transferred to a separatory funnel and the organic layer was driedover sodium sulfate and evaporated to give about 25 g of dark red oil.This oil was redissolved in ethanol (100 mL), and to the resultingstirred solution was added concentrated hydrochloric acid (10 mL). Themixture immediately formed a hard solid. Additional ethanol (100 mL) andconcentrated hydrochloric acid (10 mL) were added, and after stirringfor a few minutes, the resulting precipitate was collected byfiltration, washed with ethanol, and air-dried. The precipitate washeated to boiling with methanol (200 mL), and the mixture was allowed tocool to ambient temperature and stand overnight. The precipitate wascollected by filtration, washed with methanol, and dried under vacuum toafford 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride as anoff-white solid (7.05 g, 23% yield).

Step B: Preparation of tert-butyl7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a stirredsuspension of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.00g, 32.6 mmol) in dichloromethane (150 mL) at ambient temperature wasadded triethylamine (9.55 mL, 68.5 mmol) To the resulting solution wasadded di-tert-butyl dicarbonate (7.83 g, 35.9 mmol). The resultingsolution was stirred at ambient temperature for 90 minutes, thenconcentrated. The residue was partitioned between ethyl acetate (100 mL)and 1M citric acid (100 mL). The organic layer was washed with brine (50mL), dried over sodium sulfate and concentrated to afford tert-butyl7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate as a brown oil (9.43g, 104% yield).

Step C: Preparation of tert-butyl7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate: A solution oftert-butyl 7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (9.4 g, 34mmol) in ethanol (150 mL) was treated with 10% palladium on carbon (0.5g), and the resulting mixture was hydrogenated on a Parr shaker at aninitial pressure of 40 psi for 30 minutes. The catalyst was removed byfiltration through a glass microfibre filter, and the filtrate wasconcentrated. The residue was purified by chromatography on silica gel,eluting with 75/25 to 70/30 hexanes/ethyl acetate, to afford tert-butyl7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate as a yellow oil (6.6g, 79% yield).

Step D: Preparation of tert-butyl7-(4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate:To a stirred solution of4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (86 mg, 0.24mmol) in N,N-dimethylformamide (0.5 mL) at ambient temperature was addeda 0.6M solution of 7-aza-1-hydroxybenzotriazole in N,N-dimethylformamide(0.5 mL, 0.30 mmol), followed by solid1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.27mmol). The resulting solution was stirred at ambient temperature for 1hour. A solution of tert-butyl7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (66 mg, 0.27 mmol) inN,N-dimethylformamide (0.5 mL) was added. The resulting solution wasstirred in an oil bath set to 50° C. for 21 hours. The solution wascooled to ambient temperature and diluted with water (15 mL). Afterstirring for a few minutes, the resulting precipitate was collected byfiltration, washed with water, and dried under vacuum. This crude solidwas purified by chromatography on silica gel, eluting with 50/50hexanes/ethyl acetate, to afford tert-butyl7-(4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylateas an orange oil (84 mg, 59% yield).

Step E: Preparation of7-(4-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid: To a stirred solution of tert-butyl7-(4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate(84 mg, 0.14 mmol) in a mixture of methanol (1 mL) and tetrahydrofuran(0.5 mL) was added 2M sodium hydroxide (0.36 mL, 0.72 mmol). Theresulting solution was stirred at ambient temperature for 1 hour, thenconcentrated. The residue was partitioned between ethyl acetate (10 mL)and 1M hydrochloric acid (5 mL). The organic layer was dried over sodiumsulfate and concentrated to afford7-(4-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid as an orange oil (40 mg, 49% yield).

Step F: Preparation of6-cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid hydrochloride: To a stirred solution of7-(4-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid (40 mg, 0.070 mmol) in dioxane (1 mL) at ambient temperature wasadded a 4M solution of hydrogen chloride in dioxane (2 mL). Theresulting solution was stirred at ambient temperature for 90 minutes.Some dark material had separated from the cloudy reaction mixture, andthe supernatant was concentrated to afford6-cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid hydro-chloride as a light tan solid (30 mg, 84% yield). MS (apci)m/z=470.2 (M−Cl).

EXAMPLE 46 Sodium6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6,8-dichloro-7-hydroxychroman-4-carboxylate: To a mixture of ethyl6-chloro-7-hydroxychroman-4-carboxylate (Preparation 1) (50 g, 194.79mmol), diisobutylamine (2.72 ml, 15.58 mmol), and toluene (500 ml) wasadded SO₂Cl₂ (16.43 ml, 204.53 mmol) at ambient temperature. The mixturewas heated to 70° C. for 1 hour. The mixture was washed with water andsaturated aqueous NaHCO₃ solution (3×100 ml). The combined organicextracts were washed with brine (250 mL), dried over MgSO₄, filtered,and concentrated under reduced pressure to provide an oil. The crude oil(˜60 g) was purified on silica gel (EtOAc in hexanes gradient) toprovide 48.5 g of the title compound as a solid (86%).

Step B: Preparation of tert-butyl 4-fluoro-3-nitrobenzoate: To a 2 Lhigh pressure vessel were added 4-fluoro-3-nitrobenzoic acid (25 g, 135mmol), dimethylformamide di-t-butylacetal (162 ml, 675 mmol), andtoluene (200 ml). The vessel was sealed and heated to 100° C. for 20hours. The mixture was cooled to ambient temperature. The mixture wastransferred to 100 mL of EtOAc and 100 ml of 1N HCl and the layers wereseparated. The organic layer was washed with 1N HCl, water, and brine,dried over MgSO₄, filtered through a medium frit filter, andconcentrated. The crude was purified on silica gel (EtOAc in hexanesgradient) to provide 5.1 g of the title compound were obtained as lightyellow solid (16%).

Step C: Preparation of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dichlorochroman-4-carboxylate:A mixture of ethyl 6,8-dichloro-7-hydroxychroman-4-carboxylate (35 g,120.22 mmol), tert-butyl 4-fluoro-3-nitrobenzoate (31.1 g, 128.93 mmol),K₂CO₃ (24.923 g, 180.33 mmol), and 1-methyl-2-pyrrolidinone (500 mL) waspurged with Argon (bubbled through) for 15 minutes. The mixture washeated to 80° C. for 4 hours under Argon atmosphere. The mixture wascooled to ambient temperature and poured into 3 liters of water. The pHwas adjusted to pH 2 by addition of concentrated HCl (4×10 ml). A solidprecipitated out as HCl was added and gas evolution was observed. Thecrude mixture was filtered and the solid was dissolved in EtOAc (1liter). The EtOAc solution was washed with 2N HCl solution (200 ml),water (2×200 ml), and brine (200 ml), dried over MgSO₄, filtered, andconcentrated to provide 64.1 g of the title compound as a dark solid(104%).

Step D: Preparation of ethyl7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate:A mixture of ethyl7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dichlorochroman-4-carboxylate(61.593 g, 120.22 mmol), THF (500 ml), and saturated NH4Cl solution (500ml) was purged with Argon for 10 minutes. Zn dust (78.612 g, 1202.2mmol) was added and the mixture was stirred at ambient temperature for 1hour under Argon atmosphere. The reaction was slightly exothermic. Themixture was diluted with EtOAc (500 ml) and filtered. The filtered solidwas rinsed with EtOAc (250 ml). The filtrate was transferred to a 3 Lseparatory funnel. The layers were separated and the organic layer waswashed with brine (250 ml). The organic layer was dried over MgSO₄,filtered, and concentrated. The crude residue was purified on silica gel(EtOAc in hexanes gradient) to provide 45.6 g of the title compound asan oil (79%).

Step E: Preparation of ethyl7-(4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate: Toa 2 L four neck round bottomed flask equipped with a thermocouple, acondenser, and an addition funnel were added DMF (200 ml) and isobutylnitrite (30.8 ml, 260 mmol). The mixture was heated to 70° C. To thepreheated mixture was added a solution of ethyl7-(2-amino-4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate(50.2 g, 104 mmol) in DMF (200 ml) over a period of 15 minutes. Thereaction was slightly exothermic and gas evolution was observed. Themixture was stirred at 70° C. for 1.5 hours and cooled to ambienttemperature. The mixture was transferred to a separatory funnelcontaining 2 liters of water. The mixture was extracted with EtOAc (500ml, 2×250 ml). The combined extracts were washed with water (500 ml,2×250 ml) and brine (250 ml), dried over MgSO₄, filtered, andconcentrated. The residue was purified on silica gel (EtOAc in hexanesgradient) to provide 45.1 g of the title compound as a very viscous oil(93%).

Step F: Preparation of4-(6,8-dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid:

Ethyl7-(4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate(45.1 g, 96.5 mmol) was dissolved in dichloromethane (500 ml).Trifluoroacetic acid (100 ml) was added slowly to the solution. Themixture was stirred for 2 hours at ambient temperature. The crudemixture was concentrated and the residue was dissolved in EtOAc (500ml). The EtOAc solution was washed with saturated NaHCO₃ (3×100 ml) andbrine (250 ml), dried over MgSO₄, filtered, and concentrated to provide40.3 g of the title compound as a light brown solid (102%).

Step G: Preparation of ethyl6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6,8-Dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (22.96 g,55.832 mmol) was dissolved in dichloromethane (200 ml) and DMF (0.2 ml).Oxalyl chloride (8.6 ml, 98.585 mmol) was added slowly over a period of30 minutes at ambient temperature. The crude mixture was concentratedunder reduced pressure. Dry dichloromethane (200 ml) was added and themixture was cooled in an ice bath. 2-(4-Chlorophenyl)ethylamine (8.5413ml, 61.415 mmol) and diisopropylethylamine (11.701 ml, 66.999 mmol) wereadded sequentially to the mixture. The mixture was stirred in an icebath for 10 minutes and warmed to ambient temperature. The crude mixturewas washed with 1N HCl (100 ml), water (2×50 ml), and brine (50 ml),dried over MgSO₄, filtered through GF paper, and concentrated to provide30.1 g of a light brown solid after drying under high vacuum for 2hours. The crude solid was recrystallized from hot EtOAc-hexanes toprovide 26.8 g of the title compound as a light brown solid (87%).

Step H: Preparation of6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Ethyl6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(26.8 g, 48.83 mmol) was dissolved in 200 proof EtOH (50 ml)—THF (170ml). 6N NaOH solution (12.21 ml, 73.25 mmol) was added to the mixture atambient temperature. The mixture was stirred for 1 hour at ambienttemperature. The mixture was transferred to a separatory funnel. 1N HClsolution (97.66 ml, 97.66 mmol) was added to the separatory funnel andEtOAc (100 ml) was added. The mixture was shaken and stood for layerseparation. The layers were separated and the organic layer was washedwith water and brine (100 ml), dried over MgSO₄, filtered, andconcentrated to provide 28 g of foamy brown solid after drying underhigh vacuum. The crude solid was recrystallized from THF-hexanes toprovide 22.8 g of the title compound as a white solid (89%).

Step I: Preparation of sodium6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:6,8-Dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (22.78 g, 43.26 mmol) was dissolved in THF(100 ml) and 0.5M NaOMe solution in MeOH (86.52 ml, 43.26 mmol) wasadded at ambient temperature. The mixture was stirred for 1 hour andconcentrated. A very thick light brown solid was obtained. The crudesolid was treated with EtOH-hexanes and filtered to provide 23.4 g ofthe title compound as a white solid (99%). MS (apci) m/z=520.1(M+2H—Na).

EXAMPLE 477-(4-((2-Phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid

Step A: Preparation of methyl7-(4-((2-phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate:To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoicacid (Preparation 2) (21.8 mg, 0.0617 mmol) in dichloromethane (1 ml)with a drop of DMF was added oxalyl chloride (2M in dichloromethane)(0.0370 ml, 0.0740 mmol). Gas evolution was observed. The mixture wasstirred for 0.5 hours at ambient temperature. Triethylamine (0.0430 ml,0.3085 mmol) and 2-phenylcyclopropanamine, hemisulfate (28.11 mg, 0.1542mmol) were added sequentially to the mixture. The mixture was stirredfor 17 hours at ambient temperature. The crude mixture was purified onsilica gel (MeOH in dichloromethane gradient) to provide 25.9 mg of thetitle compound as a thin film (90%).

Step B: Preparation of7-(4-((2-phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid: Methyl7-(4-((2-phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate(25.9 mg, 0.0553 mmol) was dissolved in THF (1.5 ml) and 1MLiOH-monohydrate solution in water (0.111 ml, 0.111 mmol) was added. Themixture was stirred for 17 hours at ambient temperature. A few drops oftrifluoroacetic acid were added to the mixture and the mixture waspurified on silica gel (MeOH in dichloromethane gradient with 1% aceticacid) to provide 7.7 mg of the title compound as a thin film (30%). MS(apci) m/z=453.0 (M−H).

EXAMPLE 487-(4-((3-Methoxyphenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid

Prepared according to Example 47, substituting 3-methoxyphenethylaminefor 2-phenylcyclopropanamine in step A to provide 9.3 mg of the titlecompound (72%). MS (apci) m/z−470.9 (M−H).

EXAMPLE 497-(4-((4-Fluorophenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid

Prepared according to Example 47, substituting 4-Fluorophenethylaminefor 2-phenylcyclopropyanamine in Step A to provide 8.7 mg of the titlecompound (70%). MS (apci) m/z=458.7 (M−H).

EXAMPLE 507-(4-((4-(Trifluoromethyl)phenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid

Prepared according to Example 47, substituting4-Trifluoromethyl-phenethylamine for 2-phenylcyclopropyanamine in Step Ato provide 5.0 mg of the title compound (47%).

EXAMPLE 517-(4-((2-(4-Chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid

Step A: Preparation of ethyl 2-(4-chlorophenyl)cyclopropanecarboxylate:To a mixture of 4-chlorostyrene (1.20 ml, 10.0 mmol), Rh₂(OAc)₄ (0.221g, 0.500 mmol), and toluene (20 ml) was added ethyl diazoacetate (1.09ml, 10.50 mmol). Gas evolution was observed. The mixture was heated to80° C. for 1 hour. The mixture was purified on silica gel (EtOAc inhexanes gradient) to provide 0.216 g of the title compound as an oil(9%).

Step B: Preparation of 2-(4-chlorophenyl)cyclopropanecarboxylic acid:Ethyl 2-(4-chlorophenyl)-cyclopropanecarboxylate (0.210 g, 0.935 mmol)was placed in a 50 ml flask and dissolved in EtOH (5 ml). NaOMe in MeOH(25%, 0.808 g, 3.74 mmol) was added to the mixture. The mixture washeated for 17 hours under reflux and then concentrated. The residue wasdissolved in MeOH (10 ml), and 1M solution of LiOH—H₂O (3.74 ml, 3.74mmol) was added. The methanol was removed under reduced pressure. Theresidue was diluted with water (10 ml) and washed with EtOAc (10 ml).The aqueous layer was acidified by 1N HCl (10 ml) to pH 1 and a solidprecipitated out of solution. The mixture was extracted with EtOAc (3×10ml) and the combined extracts were dried over MgSO₄, filtered, andconcentrated to provide 181 mg of the title compound as a solid (98%).The crude solid was used in the next step without further purification.

Step C: Preparation of tert-butyl2-(4-chlorophenyl)cyclopropylcarbamate: A mixture of2-(4-chlorophenyl)cyclopropanecarboxylic acid (100 mg, 0.509 mmol),diphenylphosphoryl azide (0.1209 ml, 0.559 mmol), triethylamine (0.106ml, 0.763 mmol), and t-BuOH (2 ml) was heated at 90° C. under nitrogenatmosphere 17 hours. The mixture was concentrated, diluted with EtOAc(20 ml), and washed with saturated K₂CO₃ solution (10 ml). The EtOAclayer was dried over MgSO₄, filtered, concentrated, and dried under highvacuum for 17 hours to provide 300 mg of a light brown solid. The crudesolid was purified on silica gel (EtOAc in hexanes gradient) to provide64.7 mg of the title compound as a solid (47.5%).

Step D: Preparation of 2-(4-chlorophenyl)cyclopropanamine hydrochloride:tert-Butyl 2-(4-chlorophenyl)cyclopropylcarbamate (51.9 mg, 0.1938 mmol)was dissolved in Dichloromethane (1 ml) and 4M HCl solution in dioxane(0.4846 ml, 1.938 mmol) was added. The mixture was stirred for 3 hoursat ambient temperature, during which time a white solid precipitated outof solution. The crude mixture was concentrated and chased with EtOAc(2×10 ml). The residual fine solid was dried under high vacuum toprovide 39.2 mg of the title compound as a solid (99%).

Step E: Preparation of methyl 7-(4-((2-(4-chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate: Amixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 2) (0.041 g, 0.116 mmol),1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.0245g, 0.128 mmol), 1-hydroxybenzotriazole monohydrate (0.0195 g, 0.128mmol), and 1,2-dichloroethane (1 ml) was stirred at room temp for 0.5hours. A mixture of 2-(4-chlorophenyl)cyclopropanamine hydrochloride(0.0261 g, 0.128 mmol) and triethylamine (0.0809 ml, 0.580 mmol) in1,2-dichloroethane (1 ml) was added to the activated acid mixture. Themixture was stirred at ambient temperature for 1 hour. The crude mixturewas directly purified on silica gel (EtOAc in hexanes gradient) toprovide 50.7 mg of the title compound as a thin film (87%).

Step F: Preparation of7-(4-((2-(4-chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid: methyl7-(4-((2-(4-chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate(50.7 mg, 0.101 mmol) was dissolved in THF (3 ml). A 1M solution ofLiOH—H₂O (0.202 ml, 0.202 mmol) was added and the mixture was stirredfor 17 hours at ambient temperature. HCl (4M in dioxane) (0.0756 ml,0.302 mmol) was added to the mixture. The solution was stirredadditional 30 minutes and concentrated. The residue was purified onsilica gel (MeOH in dichloromethane with 1% acetic acid gradient) toprovide 47 mg of the title compound as a solid (95%). MS (apci)m/z=486.7 (M−H).

EXAMPLE 527-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid

Step A: Preparation of methyl7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate:A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 2) (0.0308 g, 0.0871 mmol),1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.01838g, 0.0958 mmol), 1-hydroxybenzotriazole monohydrate (0.0146 g, 0.095mmol), and 1,2-dichloroethane (1 ml) was stirred at ambient temperaturefor 20 minutes. A mixture of chroman-3-amine hydrochloride (0.01780 g,0.09589 mmol), triethylamine (0.06075 ml, 0.435 mmol), and1,2-dichloroethane (1 ml) was added to the activated acid and themixture was stirred for 17 hours at ambient temperature. The crudemixture was purified on silica gel (MeOH in dichloromethane gradient) toprovide 27.6 mg of the title compound as a foamy film (65%)

Step B: Preparation of7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid:Methyl7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate(27.6 mg, 0.0570 mmol) was dissolved in THF (3 ml) and 1M solution ofLiOH—H₂O (114 μL, 0.114 mmol) was added. The mixture was stirred for 17hours at ambient temperature. The mixture was quenched with 4M HCldioxane (42.7 μL, 0.171 mmol). The crude mixture was purified on silicagel (MeOH in dichloromethane with 1% acetic acid gradient) to provide21.2 mg of the title compound as white a solid (79%). MS (apci)m/z=471.0 (M+H).

EXAMPLE 536-Cyano-7-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl7-(4-((6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate:A mixture of 4-(6-cyano-4-(methoxycarbonyl)-chroman-7-yloxy)benzoic acid(Preparation 2) (0.0297 g, 0.0841 mmol),1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.0177g, 0.0925 mmol), 1-hydroxybenzotriazole monohydrate (0.0142 g, 0.0925mmol), and 1,2-dichloroethane (1 ml) was stirred at ambient temperaturefor 20 minutes. A mixture ofchroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride(0.0197 g, 0.0924 mmol), triethylamine (0.0585 ml, 0.4203 mmol)), and1,2-dichloroethane (1 ml) was added to the activated acid and themixture was stirred for 17 hours at ambient temperature. The crudemixture was purified on silica gel (MeOH in dichloromethane gradient) toprovide 29.5 mg of the title compound as a foamy film (69%)

Step B: Preparation of6-cyano-7-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylicacid:7-(4-((6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate(29.5 mg, 0.0576 mmol) was dissolved in THF (3 ml) and 1M solution ofLiOH—H₂O (115 μl, 0.115 mmol) was added. The mixture was stirred for 17hours at ambient temperature. The mixture was quenched with 4M HCldioxane (43.2 μL, 0.173 mmol). The crude mixture was purified on silicagel (MeOH in dichloromethane with 1% acetic acid gradient) to provide28.9 mg of the title compound as a thin film (100%). MS (apci) m/z=499.1(M+H).

EXAMPLE 546-Cyano-7-(4-(naphthalen-1-ylmethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 53, substitutingnaphthalen-1-ylmethanamine forchroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride inStep A to provide 22.9 mg of the title compound as a thin film (92%). MS(apci) m/z=476.8 (M−H).

EXAMPLE 556-Cyano-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 53, substituting2-(naphthalen-1-yl)ethanamine forchroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride inStep A to provide 24.1 mg of the title compound as a thin film (86%). MS(apci) m/z=490.9 (M−H).

EXAMPLE 566-Cyano-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 53, substituting2-(naphthalen-2-yl)ethanamine forchroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride inStep A to provide 8.4 mg of the title compound as a thin film (49%). MS(apci) m/z=490.9 (M−H).

EXAMPLE 577-(4-(4-tert-Butylphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Prepared according to Example 53, substituting2-(4-tert-butylphenyl)ethanamine forchroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride inStep A to provide 18 mg of the title compound as a thin film (77%). MS(apci) m/z=499.1 (M−H).

EXAMPLE 587-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Prepared according to Example 53, substituting2-(Biphenyl-4-yl)ethanamine forchroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride inStep A to provide 32.5 mg of the title compound as a white solid (90%).MS (apci) m/z=519.1 (M+H).

EXAMPLE 597-(4-(2-Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid

Step A: Preparation of ethyl7-(4-(2-(biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid (Preparation 1) (50 mg, 0.133 mmol) in dichloromethane (1 ml) and adrop of DMF was added oxalyl chloride (2M in dichloromethane) (72.985μL, 0.145 mmol) at ambient temperature. Gas evolution was observed. Themixture was stirred at ambient temperature for 30 minutes.2-(Biphenyl-4-yl)ethanamine (27.488 mg, 0.139 mmol) and triethylamine(36.992 μL, 0.265 mmol) were added and the mixture was stirred for 1hour at ambient temperature. The crude mixture was purified on silicagel (MeOH in dichloromethane gradient) to provide 62.5 mg of the titlecompound as a solid (85%).

Step B: Preparation of7-(4-(2-(biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid: Ethyl7-(4-(2-(biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(62.5 mg, 0.1124 mmol) was dissolved in THF (1 ml) and 1M solution ofLiOH—H₂O (224.8 μL, 0.2248 mmol) was added. The mixture was stirred for3 days at ambient temperature. The mixture was quenched with 1M HClsolution (400 μL, 0.400 mmol). The crude mixture was purified on silicagel (MeOH in dichloromethane with 1% acetic acid gradient) to provide48.8 mg of the title compound as a white solid (82%).

Step C: Preparation of sodium7-(4-(2-(biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid (42 mg, 0.07955 mmol) was dissolved in MeOH-THF (1 ml-1 ml). A 0.5M solution of NaOMe in MeOH (159.1 μl, 0.0795 mmol) was added and themixture was stirred for few minutes. The crude mixture was concentratedand chased with EtOAc and dichloromethane to provide 44.6 mg of thetitle compound as a white solid (102%). MS (apci) m/z=528.1 (M+2H—Na).

EXAMPLE 60 Sodium6-chloro-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 59, substituting(R)-2-phenylpropan-1-amine for 2-(Biphenyl-4-yl)ethanamine in step A toprovide 78.1 mg of the title compound as a white solid (99%). ¹H NMR(400 MHz, DMSO-D₆) δ 8.42 (t, J=5.9 Hz, 1H), 7.79-7.76 (m, 2H), 7.54 (s,1H), 7.32-7.23 (m, 4H), 7.21-7.17 (m, 1H), 6.92-6.88 (m, 2H), 6.50 (s,1H), 4.23-4.17 (m, 1H), 4.12-4.07 (m, 1H), 3.44-3.33 (m, 2H), 3.20-3.16(m, 1H), 3.08-3.03 (m, 1H), 2.23-2.15 (m, 1H), 1.79-1.70 (m, 1H), 1.21(d, J=7.0 Hz, 3H).

EXAMPLE 61 Sodium6-chloro-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 59, substituting(S)-2-phenylpropan-1-amine for 2-(Biphenyl-4-yl)ethanamine in step A toprovide 79.7 mg of the title compound as a white solid (97%). ¹H NMR(400 MHz, DMSO-D₆) δ 8.42 (t, J=5.9 Hz, 1H), 7.79-7.76 (m, 2H), 7.54 (s,1H), 7.32-7.23 (m, 4H), 7.21-7.17 (m, 1H), 6.92-6.88 (m, 2H), 6.50 (s,1H), 4.23-4.17 (m, 1H), 4.12-4.07 (m, 1H), 3.44-3.33 (m, 2H), 3.20-3.16(m, 1H), 3.08-3.03 (m, 1H), 2.23-2.15 (m, 1H), 1.79-1.70 (m, 1H), 1.21(d, J=7.0 Hz, 3H).

EXAMPLE 62 Sodium6-chloro-7-(4-(2-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 59, substitutingp-Chloro-β-methyl-phenethylamine-HCl salt for2-(Biphenyl-4-yl)ethanamine in step A to provide 92.3 mg of the titlecompound as a white solid (101%). ¹H NMR (400 MHz, DMSO-D₆) δ 8.41 (t,J=5.9 Hz, 1H), 7.78-7.74 (m, 2H), 7.54 (s, 1H), 7.36-7.33 (m, 2H),7.29-7.25 (m, 2H), 6.92-6.88 (m, 2H), 6.50 (s, 1H), 4.23-4.16 (m, 1H),4.13-4.06 (m, 1H), 3.42-3.33 (m, 2H), 3.21-3.16 (m, 1H), 3.09-3.03 (m,1H), 2.22-2.15 (m, 1H), 1.79-1.70 (m, 1H), 1.21 (d, J=7.0 Hz, 3H).

EXAMPLE 63 Sodium6-chloro-7-(4-(2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 59, substituting 2-Methoxyphenethylaminefor 2-(Biphenyl-4-yl)ethanamine in step A to provide 38.8 mg of thetitle compound as a white solid (107%). MS (apci) m/z=482.0 (M+2H—Na).

EXAMPLE 64 Sodium6-chloro-7-(4-(2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 59, substituting2-(trifluoromethoxy)phenethylamine for 2-(Biphenyl-4-yl)ethanamine instep A to provide 46 mg of the title compound as a white solid (101%).MS (apci) m/z=536.1 (M+2H—Na).

EXAMPLE 65 Sodium6-chloro-7-(4-(2-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 59, substituting 2-phenoxyphenethylaminefor 2-(Biphenyl-4-yl)ethanamine in step A to provide 48.3 mg of thetitle compound as a white solid (111%). MS (apci) m/z=544.0 (M+2H—Na).

EXAMPLE 666-Cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl6-cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate:A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 2) (50 mg, 0.1415 mmol),1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (32.55mg, 0.170 mmol), 1-hydroxybenzotriazole monohydrate (26.01 mg, 0.170mmol), and 1,2-dichloroethane (2 ml) was stirred at ambient temperaturefor 30 minutes. To the mixture was added 3′,4′-dimethylbiphenyl-3-aminehydrochloride (39.69 mg, 0.170 mmol) and triethylamine (98.62 μl, 0.707mmol) and the mixture was stirred for 2 days at ambient temperature. Thecrude mixture was purified on silica gel (EtOAc in hexanes gradient) toprovide 36 mg of the title compound as a thin film (48%).

Step B: Preparation of6-cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Methyl6-cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate(36 mg, 0.06759 mmol) was dissolved in THF (2 ml) and 1M solution ofLiOH—H₂O (135.2 μL, 0.135 mmol) was added. The mixture was stirred for17 hours at ambient temperature. The mixture was quenched with 4M HCldioxane (50.70 μL, 0.203 mmol). The crude mixture was purified on silicagel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 31mg of the title compound as a thin film (90%). MS (apci) m/z=519.1(M+H).

EXAMPLE 677-(4-(Biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid

Step A: Preparation of methyl7-(4-(biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate: To asolution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 2) (50 mg, 0.142 mmol) and a drop of DMF in dichloromethane(2 ml) was added oxalyl chloride (2M in dichloromethane) (84.91 μL,0.170 mmol) at ambient temperature. Gas evolution was observed. Themixture was stirred for 1 hour at ambient temperature. Biphenyl-3-amine(28.74 mg, 0.170 mmol) in dichloromethane (1 ml) and triethylamine(59.172 μL, 0.424 mmol) were added to the activated acid. The mixturewas stirred for 1 hour at ambient temperature. The crude mixture waspurified on silica gel (EtOAc in hexanes gradient) to provide 55.6 mg ofthe title compound as a thin film (78%).

Step B: Preparation of7-(4-(biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid:To a solution of methyl7-(4-(biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (55.6mg, 0.1102 mmol) in THF (2 ml) was added 1M solution of LiOH—H₂O (220.4μl, 0.2204 mmol). The mixture was stirred for 1 hour at ambienttemperature. The mixture was quenched with 4M HCl dioxane (82.65 μl,0.331 mmol). The crude mixture was purified on silica gel (MeOH indichloromethane with 1% acetic acid gradient) to provide 40.4 mg of thetitle compound as a thin film (75%). MS (apci) m/z=491.1 (M+H).

EXAMPLE 687-(4-(Biphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid

Prepared according to Example 67, substituting biphenyl-4-amineforbiphenyl-3-amine to provide 41.3 mg of the title compound as a whitesolid (88%). MS (apci) m/z=489.3 (M−H).

EXAMPLE 697-(4-(4′-Chlorobiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Prepared according to Example 67, substituting 4′-Chlorobiphenyl-4-aminefor biphenyl-3-amine to provide 40.1 mg of the title compound as a whitesolid (90%). MS (apci) m/z=522.8 (M−H).

EXAMPLE 706-Cyano-7-(4-(3-(2-methylpyrimidin-4-yl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 67, substituting3-(2-methylpyrimidin-4-yl)aniline for biphenyl-3-amine to provide 51.5mg of the title compound as a white solid (90%). MS (apci) m/z=507.3(M+H).

EXAMPLE 716-Chloro-7-(4-(4′-chloro-6-fluorobiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of ethyl7-(4-(3-bromo-4-fluorophenylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (0.214 g, 0.569 mmol) was dissolved in1,2-dichloroethane (2 ml) and a drop of DMF was added. To the mixturewas added oxalyl chloride (2M in dichloromethane) (0.313 ml, 0.626mmol). Gas evolution was observed. The mixture was stirred for 2 hoursat ambient temperature. A solution of 3-bromo-4-fluoroaniline (0.113 g,0.597 mmol) and triethylamine (0.158 ml, 1.138 mmol) in dichloromethane(1 ml) was added to the acid chloride solution. The mixture was stirredfor 0.5 hour and the crude mixture was purified on silica gel (EtOAc inhexanes gradient) to provide 0.2656 g of the title compound as a whitesolid (85%).

Step B: Preparation of ethyl6-chloro-7-(4-(4′-chloro-6-fluorobiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate:A mixture of ethyl7-(4-(3-bromo-4-fluorophenylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(54.8 mg, 0.0998 mmol), 4-chlorophenylboronic acid (20.299 mg, 0.129mmol), Na₂CO₃ (31.75 mg, 0.299 mmol),tetrakis(triphenylphosphine)palladium(0) (5.769 mg, 0.0049 mmol), water(0.1 ml), and toluene (1 ml) in a vial was purged with Argon for fewminutes and heated for 17 hours at 125° C. The crude mixture waspurified on silica gel (EtOAc in hexanes gradient) to provide 41.4 mg ofthe title compound as a foamy solid (71%).

Step C: Preparation of6-cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: A mixture of ethyl6-chloro-7-(4-(4′-chloro-6-fluorobiphenyl-3-ylcarbamoyl)phenoxy)-chroman-4-carboxylate(41.4 mg, 0.07133 mmol), 1M solution of LiOH—H₂O (142.7 μL, 0.1427mmol), and THF (1 ml) was stirred for 17 hours at ambient temperature.The mixture was quenched with 1M HCl (214.0 μL, 0.2140 mmol). The crudemixture was purified on silica gel (MeOH in dichloromethane with 1%acetic acid gradient) to provide 32.9 mg of the title compound as awhite solid (83%). MS (apci) m/z=552.1 (M+H).

EXAMPLE 726-Cyano-7-(4-(1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl6-cyano-7-(4-(1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation2) (10 mg, 0.028 mmol) was diluted with DCM (500 uL) followed by theaddition of oxalyl chloride in DCM (2M) (0.017 ml, 0.034 mmol) and 1drop of DMF. After stirring for 30 minutes,1,2,3,4-tetrahydro-naphthalen-2-ylamine (8.3 mg, 0.057 mmol) and DIEA(0.020 mL, 0.11 mmol) were added. After stirring for 2 hours, thereaction was loaded directly onto a biotage 12i cartridge and elutedwith 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(10 mg, 73% yield).

Step B: Preparation of6-cyano-7-(4-(1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Methyl7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(10 mg, 0.021 mmol) was diluted with THF (500 μL) followed by theaddition of NaOH (0.12 ml, 0.12 mmol) and methanol (100 μL). Afterstirring for 1 hour, the reaction was diluted with ethyl acetate and 2NHCl. The layers were separated and the organic layer was dried overMgSO₄, filtered and concentrated to yield7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid (3.0 mg, 31% yield). MS (ESI)=469.0 (M+H).

EXAMPLE 737-(4-(5-Chloro-2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Prepared according to the method of Example 72, substituting5-chloro-2,3-dihydro-1H-inden-2-amine for1,2,3,4-Tetrahydro-naphthalen-2-ylamine. MS (ESI)=489.0 (M+H).

EXAMPLE 747-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid

Prepared according to the method of Example 72, substituting4-chloroaniline for 1,2,3,4-Tetrahydro-naphthalen-2-ylamine. MS(ESI)=448.9 (M+H).

EXAMPLE 756-Cyano-7-(4-(4-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 72, substituting4-(trifluoromethyl)aniline for 1,2,3,4-Tetrahydro-naphthalen-2-ylamine.MS (ESI)=482.9 (M+H).

EXAMPLE 766-Cyano-7-(4-(naphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid

Prepared according to the method of Example 72, substitutingnaphthalen-2-amine for 1,2,3,4-Tetrahydro-naphthalen-2-ylamine. MS(ESI)=464.9 (M+H).

EXAMPLE 77 Sodium6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid(Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followedby the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) andDMF (1 drop). After stirring for 10 minutes,3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl,0.39 mmol) were added and the reaction was stirred at ambienttemperature for 2 hours. The reaction was loaded directly onto a biotage25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethylacetate/hexanes to yield ethyl6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate(80 mg, 0.15 mmol, 85% yield).

Step B: Preparation of6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol) wasdiluted with THF (1 mL) followed by the addition of NaOH (757 μL, 0.76mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction wasdiluted with ethyl acetate and 2N HCl. The layers were separated and theorganic layer was dried over MgSO₄, filtered and concentrated to yield6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylicacid (76 mg, 0.15 mmol, 100% yield).

Step C: Preparation of sodium 6-chloro-7-(4-(3-(4-chlorophenol)propylcarbamoyl)phenoxy)chroman-4-carboxylate:6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic acid (76 mg, 0.15 mmol) wasdiluted with THF (500 μL) followed by the addition of NaOMe (304 μl,0.15 mmol). After stirring for 2 hours, the reaction was concentratedunder reduced pressure to yield6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylicacid (50 mg, 0.100 mmol, 66% yield). MS (ESI)=500.2 (M−Na+2H).

EXAMPLE 78 Sodium6-chloro-7-(4-(3-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting3-phenylpropan-1-amine for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=466.1 (M−Na+2H).

EXAMPLE 79 Sodium6-chloro-7-(4-(2-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2-chlorophenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=486.1 (M−Na+2H).

EXAMPLE 80 Sodium6-chloro-7-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2,6-dichlorophenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine.MS (ESI)=520.1 (M−Na+2H).

EXAMPLE 81 Sodium6-chloro-7-(4-(2,4-difluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2,4-difluorophenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine.MS (ESI)=488.1 (M−Na+2H).

EXAMPLE 82 Sodium6-chloro-7-(4-(2-chloro-6-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2-chloro-6-fluorophenyl)ethanamine for3-(4-chlorophenyl)propan-1-amine. MS (ESI)=504.2 (M−Na+2H).

EXAMPLE 83 Sodium6-chloro-7-(4-(3-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting3-(2-aminoethyl)phenol for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=468.0 (M−Na+2H).

EXAMPLE 84 Sodium6-chloro-7-(4-(4-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting4-(2-aminoethyl)phenol for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=468.0 (M−Na+2H).

EXAMPLE 85 Sodium6-chloro-7-(4-(4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(4-fluorophenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=470.1 (M−Na+2H).

EXAMPLE 86 Sodium6-chloro-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(naphthalen-1-yl)ethanamine for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=502.1 (M−Na+2H).

EXAMPLE 87 Sodium6-chloro-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(naphthalen-2-yl)ethanamine for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=502.1 (M−Na+2H).

EXAMPLE 88 Sodium6-chloro-7-(4-(2,5-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2,5-dimethoxyphenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine.MS (ESI)=512.0 (M−Na+2H).

EXAMPLE 89 Sodium6-chloro-7-(4-(2,3-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2,3-dimethoxyphenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine.MS (ESI)=512.0 (M−Na+2H).

EXAMPLE 90 Sodium7-(4-(5-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(5-bromo-2-methoxyphenyl)ethanamine for3-(4-chlorophenyl)propan-1-amine. MS (ESI)=562.0 (M−Na+2H).

EXAMPLE 91 Sodium7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Prepared according to the method of Example 77, substituting2-(2-bromophenyl)ethanamine for 3-(4-chlorophenyl)propan-1-amine. MS(ESI)=530.0 (M−Na+2H).

EXAMPLE 92 Sodium7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Step A: Preparation of ethyl7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (200 mg, 0.531 mmol) was diluted with DCM (3 mL)followed by the addition of oxalyl chloride in DCM (2M) (292 μl, 0.584mmol) and DMF (1 drop). After stirring for 20 minutes,2-(2-bromophenyl)ethanamine (117 mg, 0.584 mmol) and DIEA (203 μl, 1.17mmol) were added and the reaction was stirred at ambient temperature for12 hours. The reaction was loaded directly onto a biotage 25 cartridgeand eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes toyield ethyl7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(268 mg, 0.480 mmol, 90.3% yield).

Step B: Preparation of ethyl7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:Ethyl7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(29 mg, 0.052 mmol, 79% yield), phenylboronic acid (10 mg, 0.086 mmol),Na₂CO₃ (21 mg, 0.20 mmol) and Pd(PPh₃)₄ (7.7 mg, 0.0066 mmol) werecombined in a vial, diluted with dioxane (800 μL), purged with Argon,sealed and heated to 110° C. and stirred for 12 hours. The reaction wasallowed to cool and loaded directly onto a biotage 25 cartridge elutingwith 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yieldethyl7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(29 mg, 0.052 mmol, 79% yield).

Step C: Preparation of7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid: Ethyl7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(29 mg, 0.052 mmol) was diluted with THF (1 mL) followed by the additionof NaOH (261 μL, 0.26 mmol) and ethanol (500 μL). After stirring for 2hours, the reaction was diluted with ethyl acetate and 2N HCl. Thelayers were separated and the organic layer was dried over MgSO₄,filtered and concentrated to yield7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid (26 mg, 0.049 mmol, 94% yield).

Step D: Preparation of sodium7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:7-(4-(2-(Biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid (26 mg, 0.049 mmol) was diluted with THF (500 μL) followed by theaddition of NaOMe (98 μL, 0.049 mmol). After stirring for 2 hours, thereaction was concentrated and placed under high vacuum for 12 hours toyield7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid (15 mg, 0.028 mmol, 58% yield) as a white foam. MS (ESI)=528.2(M−Na+2H).

EXAMPLE 93 Sodium6-chloro-7-(4-(2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 92, substitutingphenylboronic acid in Step B with cyclopropylboronic acid. MS(ESI)=492.0 (M−Na+2H).

EXAMPLE 94 Sodium6-chloro-7-(4-(2-(4′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 92, substitutingphenylboronic acid in Step B with 4-chlorophenylboronic acid. MS(ESI)=562.1 (M−Na+2H).

EXAMPLE 95 Sodium6-chloro-7-(4-(2-(3′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 92, substitutingphenylboronic acid in Step B with 3-chlorophenylboronic acid in Step B.MS (ESI)=562.1 (M−Na+2H).

EXAMPLE 96 Sodium6-chloro-7-(4-(2-(2′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 92, substitutingphenylboronic acid in Step B with 2-chlorophenylboronic acid. MS(ESI)=562.1 (M−Na+2H).

EXAMPLE 97 Sodium6-chloro-7-(4-(2-chloro-4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 2-(2-chloro-4-fluorophenyl)ethanamine:2-(2-chloro-4-fluorophenyl)acetamide (400 mg, 2.13 mmol) was dilutedwith THF (2 mL), placed under nitrogen and cooled to 0° C. LAH (4264 μL,4.26 mmol) was added dropwise and the reaction was refluxed for 3 hours.The reaction was cooled to 0° C. and quenched with 160 μL of water, 160μL of 15% NaOH, and 530 μL of water. After stirring for 30 minutes thereaction was filtered and concentrated. The material was purified usinga biotage 25 column eluting with 2% NH₄OH/10% methanol/DCM to yield2-(2-chloro-4-fluorophenyl)ethanamine (60 mg, 0.346 mmol, 16.2% yield).

Step B: Preparation of sodium 6-chloro-7-(4-(2-chloro-4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to themethod of Example 77, substituting 2-(2-chloro-4-fluorophenyl)ethanaminefor 3-(4-chlorophenyl)propan-1-amine. MS (ESI)=504.1 (M−Na+2H).

EXAMPLE 98 Sodium6-chloro-7-(4-(2-chloro-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 2-chloro-4-(trifluoromethyl)benzaldehyde:2-Chloro-4-(trifluoromethyl)benzonitrile (500 mg, 2.43 mmol) was dilutedwith toluene (3 mL), placed under nitrogen and cooled to −78° C. DIBAL-H(4865 μL, 4.86 mmol) was added dropwise and the reaction was stirred for1 hour. The reaction was warmed to 0° C. and acetic acid (2 mL) wasadded followed by 10 mL of water. After stirring for 2 hours, thereaction was extracted twice with ethyl acetate, washed with Rochelle'ssalt, dried over MgSO₄, filtered and concentrated. The material waspurified using a biotage 25 cartridge running a gradient, 100% hexanesto 20% DCM/hexanes to yield 2-chloro-4-(trifluoromethyl)benzaldehyde(400 mg, 1.92 mmol, 78.8% yield) as a clear oil.

Step B: Preparation of (E)-2-chloro-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene: 2-chloro-4-(trifluoromethyl)benzaldehyde (400 mg, 1.92 mmol)was diluted with nitromethane (727 μl, 13.4 mmol) followed by theaddition of methylamine hydrochloride (77.7 mg, 1.15 mmol) and sodiumacetate (94.4 mg, 1.15 mmol). After stirring for 12 hours, the reactionwas loaded directly onto a biotage 25 cartridge and eluted with 5% ethylacetate/hexanes to 50% ethyl acetate/hexanes to yield(E)-2-chloro-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (160 mg, 0.636mmol, 33.2% yield).

Step C: Preparation of 2-(2-chloro-4-(trifluoromethyl)phenyl)ethanamine:(E)-2-chloro-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (160 mg, 0.636mmol) was diluted with THF (1 mL), placed under nitrogen and cooled to0° C. LAH (2544 μL, 2.54 mmol) was added dropwise and the reaction wasstirred for 5 hours warming to ambient temperature. The reaction wascooled to 0° C. and quenched with 100 μL of water, 100 μL of 15% NaOHand 300 μL water. After stirring for 1 hour, ethyl acetate and MgSO₄ wasadded. The reaction mixture was filtered and concentrated to yield2-(2-chloro-4-(trifluoromethyl)phenyl)ethanamine (60 mg, 0.268 mmol,42.2% yield).

Step D: Preparation of Sodium6-chloro-7-(4-(2-chloro-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to the method of Example 77, substituting2-(2-chloro-4-(trifluoromethyl)phenyl)ethanamine for3-(4-chlorophenyl)propan-1-amine. MS (ESI)=554.1 (M−Na+2H).

EXAMPLE 99 Sodium6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 4-chloro-2-methoxybenzaldehyde:4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe(3784 μL, 1.89 mmol) (solution in methanol), heated to 50° C. andstirred for 3 hours. The reaction was concentrated in half and loadeddirectly onto a biotage 25 cartridge eluting with 5% ethylacetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47mmol, 77.5% yield).

Step B: Preparation of (E)-4-chloro-2-methoxy-1-(2-nitrovinyl)benzene:4-Chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol) was diluted withnitromethane (556 μL, 10.3 mmol) followed by the addition of methylaminehydrochloride (59.4 mg, 0.879 mmol) and sodium acetate (72.1 mg, 0.879mmol). After stirring for 12 hours, the reaction was loaded directlyonto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes toyield (E)-4-chloro-2-methoxy-1-(2-nitrovinyl)benzene (245 mg, 1.15 mmol,78.3% yield).

Step C: Preparation of 2-(4-chloro-2-methoxyphenyl)ethanamine:(E)-4-chloro-2-methoxy-1-(2-nitrovinyl)benzene (245 mg, 1.15 mmol) wasdiluted with THF (1 mL), placed under nitrogen and cooled to 0° C. LAH(4588 μL, 4.59 mmol) was added dropwise and the reaction was stirred for5 hours warming to ambient temperature. The reaction was cooled to 0° C.and quenched with 174 μL of water, 174 μL of 15% NaOH and 522 μL water.After stirring for 1 hour, ethyl acetate and MgSO₄ was added. Thereaction mixture was filtered and concentrated to yield2-(4-chloro-2-methoxyphenyl)ethanamine (160 mg, 0.862 mmol, 75.1%yield).

Step D: Preparation of sodium 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to themethod of Example 77, substituting2-(4-chloro-2-methoxyphenyl)ethanamine for3-(4-chlorophenyl)propan-1-amine. MS (ESI)=515.9 (M−Na+2H).

EXAMPLE 100 Sodium6-chloro-7-(4-(2-chloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 99, substituting2-Chloro-4-fluorobenzaldehyde for 4-chloro-2-fluorobenzaldehyde in StepA. MS (ESI)=515.9 (M−Na+2H).

EXAMPLE 101 Sodium6-chloro-7-(4-(4-fluoro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 99, substituting 2,4-difluorobenzaldehydefor 4-chloro-2-fluorobenzaldehyde in Step A. MS (ESI)=500.1 (M−Na+2H).

EXAMPLE 102 Sodium6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 99, substituting2-Fluoro-4-(trifluoromethyl)benzaldehyde for4-chloro-2-fluorobenzaldehyde in Step A. MS (ESI)=550.0 (M−Na+2H).

EXAMPLE 103 Sodium6-chloro-7-(4-(2,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 72, substituting2,5-dichlorophenethyl amine for 1,2,3,4-tetrahydronaphthalen-2-amine. MS(apci) m/z=520 (M+2H—Na).

EXAMPLE 104 Sodium6-chloro-7-(4-(5-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 72, substituting5-chloro-2-fluorophenethyl amine for1,2,3,4-tetrahydronaphthalen-2-amine. MS (apci) m/z=502 (M+2H—Na).

EXAMPLE 105 Sodium6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid was dissolvedin 700 mL of dichloromethane containing 8 drops of DMF and cooled to 5°C. Oxalyl chloride (31 mL, 355 mmol) was added as a solution in 10 mL ofdichloromethane dropwise over 20 minutes keeping the reactiontemperature between 8 and 11° C. After stirring at ambient temperaturefor 20 hours, the solution was cooled to 0° C. and 2,4-dichlorophenethylamine (55 mL, 365 mmol) was added as a solution in 20 mL ofdichloromethane dropwise over 20 minutes keeping the reactiontemperature below 10° C. To the resulting thick, cream-colored slurrywas added diisopropyl ethyl amine (70 mL, 402 mmol) dropwise over 20minutes keeping the reaction temperature below 10° C. After 3 hours atambient temperature, the reaction mixture was diluted with 2 L ofdichloromethane and washed sequentially with three 500 mL portions of 1N HCl, two 500 mL portions of water and two 500 mL portions of brine.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to give 178 g of crude ethyl6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate.The crude material was slurried in hot ethyl acetate, cooled to ambienttemperature and the solids were collected, washing with 20% ethylacetate in hexanes. The white solids were dried under high vacuum togive ethyl6-chloro-7-(4-(2,4-dichlorophenethyl-carbamoyl)phenoxy)chroman-4-carboxylate(145 g, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=8.4 Hz, 2H),7.40 (s, 1H), 7.36 (s, 1H), 7.20 (s, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.53(s, 1H), 6.12 (t, J=5.3 Hz, 1H), 4.21-4.29 (m, 4H), 3.67-3.75 (m, 3H),3.05 (t, J=6.7 Hz, 2H), 2.30-2.35 (m, 1H), 2.05-2.14 (m, 1H), 1.31 (t,J=7.0 Hz, 3H).

Step B: Preparation of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylicacid: Ethyl6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylate(220 g, 401 mmol) was dissolved in 1.8 L of a 2:1 mixture of THF:EtOH.To the solution was added 4 N NaOH (150 mL, 600 mmol) and the reactionwas stirred at ambient temperature for 2 hours. The mixture wasconcentrated to a solid residue, diluted with 1 L of water and 1 N HCl(700 mL, 700 mmol) was added. The resulting white solids were collectedby filtration, washing with 2 L of water. The white solids were driedunder high vacuum to give6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid (207 g, 99% yield). MS (apci) m/z=520 (M−H).

Step C: Preparation of sodium6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate:6-Chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylicacid (4.50 g, 8.64 mmol) was dissolved in 25 mL of MeOH and cooled to 0°C. A 0.5 M solution of sodium methoxide in methanol (17.3 mL, 8.64 mmol)was then added and the cooling bath removed. After stirring at ambienttemperature for 1 hour, the solution was concentrated to a residue. Theresidue was mixed with 50 mL of hexanes and stirred for 1 hour. Theresulting precipitates were collected by filtration and dried under highvacuum to provide the title compound. The hexane treatment was repeatedand the resulting white powder was dried under high vacuum at 65° C. togive sodium6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate(4.7 g, 100% yield). MS (apci) m/z=518 (M+2H—Na).

EXAMPLE 106 Enantiomer 2 of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Separation of enantiomers of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylicacid:6-Chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylicacid (Example 105; 200 g) was dissolved in ethanol (21 mg/mL). Thematerial was resolved via supercritical fluid chromatography employing aCHIRALCEL® OJ-H column (3×15 cm) eluting with 35% ethanol/carbon dioxideat 100 bar, using 3 mL injections and a flow rate of 140 mL/min.Collection of fractions containing peak 2 and removal of volatilesprovided Enantiomer 2 of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid (100 g, 50% yield). MS (apci) m/z=520 (M−H). Optical rotation:[a]²⁵ _(D)=−14° (c=1.00, MeOH).

Step B: Preparation of sodium salt of Enantiomer 2 of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate:6-Chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid (peak 2, 32.4 g, 57.9 mmol) was dissolved in 300 mL of MeOH, cooledto 0° C. and sodium methoxide (0.50 M in MeOH) (116 mL, 58 mmol) wasadded. The mixture was stirred at ambient temperature for 1 hour andconcentrated to a solid residue. The residue was stirred with 800 mL ofhexanes for 20 minutes and the solids were collected by filtration,washing with excess hexanes. The white solid was dried under high vacuumat 60 to 65° C. for 3 hours to give the sodium salt of peak 2,Enantiomer 2 of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate(31.4 g, 99% yield). MS (apci) m/z=522 (M+2H—Na).

During the chiral separation described in Step A, peak 1 was isolated toprovide Enantiomer 1 of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. Chiral purity (ee)>98% as measured with a CHIRALPAK® QD-AX columnin comparison to racemic material). The sodium salt of Enantiomer 1 wasthen prepared as described in Step B. MS (apci, neg) m/z 520 (M−H). Thesodium salt of Enantiomer 1 was found to be less active than the sodiumsalt of Enantiomer 2 when tested in an assay described in Example A.

EXAMPLE 1076-Cyano-7-(4-(4′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl6-cyano-7-(4-(4′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate:In a vial were placed methyl6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate(Preparation 3) (56 mg, 0.1010 mmol), p-tolylboronic acid (17.855 mg,0.1313 mmol), Na₂CO₃ (32.121 mg, 0.3030 mmol), toluene (1 ml), and water(0.1 ml). The mixture was degassed with Argon for few minutes.Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.005 mmol) wasadded and the vial was sealed. The mixture was stirred at 100° C. for 24hours. The crude mixture was purified on silica gel (EtOAc in hexanesgradient) to provide 33.1 mg of the title compound as foamy solid (63%).

Step B: Preparation of6-cyano-7-(4-(4′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: A mixture of methyl7-(4-(4′-methylbiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(33 mg, 0.063 mmol), 1M solution of LiOH—H₂O (127.3 μl, 0.127 mmol), andTHF (1.5 ml) was stirred for 17 hours at ambient temperature. Themixture was quenched with 4M HCl dioxane (47.73 μL, 0.190 mmol). Thecrude mixture was purified on silica gel (MeOH in dichloromethane with1% acetic acid gradient) to provide 29.8 mg of the title compound as awhite solid (93%). MS (apci) m/z=505.1 (M+H).

EXAMPLE 1086-Cyano-7-(4-(3′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 107, substituting m-tolylboronic acid forp-tolylboronic acid to provide 26.9 mg of the title compound as a whitesolid (82%). MS (apci) m/z=505.1 (M+H).

EXAMPLE 1096-Cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl6-cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate:In a vial were placed methyl6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate(Preparation 3) (56 mg, 0.101 mmol), 2,3-dimethylphenylboronic acid(19.70 mg, 0.131 mmol), Na₂CO₃ (32.12 mg, 0.303 mmol), toluene (1 ml),and water (0.1 ml). The mixture was degassed with Argon for few minutes.Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.0050 mmol) wasadded and the vial was sealed. The mixture was stirred for 17 hours at100° C. The crude mixture was purified on silica gel (EtOAc in hexanesgradient) to provide 34.4 mg of the title compound as a thin film (64%).

Step B: Preparation of6-cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: A mixture of methyl7-(4-(2′,3′-dimethylbiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate(34.4 mg, 0.0645 mmol), 1M solution of LiOH—H₂O (129.7 μL, 0.129 mmol),and THF (1.5 ml) was stirred for 17 hours at ambient temperature. Themixture was quenched with 1M HCl (193.8 μL, 0.194 mmol). The crudemixture was purified on silica gel (MeOH in dichloromethane with 1%acetic acid gradient) to provide 25.2 mg of the title compound as awhite solid (75%). MS (apci) m/z=519.1 (M+H).

EXAMPLE 110 Sodium7-(4-(2-(benzo[d][1,3]-dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Step A: Preparation of ethyl7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:2-(Benzo[d][1,3]dioxol-5-yl)ethanamine (32.9 mg, 0.199 mmol) in DMF (0.1M) was treated sequentially with4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (1327 μL, 0.133 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg,0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) atambient temperature. After 16 hours, the reaction was applied directlyto a silica gel column and eluted with a gradient (20% to 80%) of ethylacetate-hexanes to provide the title compound (65 mg, 0.124 mmol, 93.5%yield) as a white solid.

Step B: Preparation of 7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid: Ethyl7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(65 mg, 0.124 mmol) was dissolved in 2:1 tetrahydrofuran-ethanol andtreated with 1.0 molar sodium hydroxide (496 μl, 0.496 mmol) at ambienttemperature. After 3 hours, the reaction was diluted with ethyl acetate,neutralized with 1.0 molar hydrochloric acid (521 μl, 0.521 mmol), andpartitioned between saturated sodium chloride aqueous solution. Theorganic layer was dried with sodium sulfate, filtered, concentrated, anddried under high vacuum to provide the title compound (61 mg, 0.123mmol, 99.2% yield) as a solid.

Step C: Preparation of sodium7-(4-(2-(benzo[d][1,3]-dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid (60 mg, 0.12 mmol), 0.1 molar in 4:1 tetrahydrofuran-methanol, wastreated with sodium methanolate (242 μl, 0.12 mmol) at ambienttemperature. After 15 minutes, the solvent was removed in vacuo. Theresulting solid was taken up in ethyl acetate and concentrated in vacuo.The solid was then taken up in 4:1 dichloromethane-hexanes andconcentrated in vacuo and dried under high vacuum to provide sodium7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(63 mg, 0.12 mmol, 101% yield) as a solid. MS (apci) m/z=495.9(M+2H—Na).

EXAMPLE 111 Sodium6-chloro-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid(Preparation 1) (50 mg, 0.133 mmol), suspended in 1.3 ml ofdichloromethane, was treated sequentially with(2,3-dihydro-1H-inden-2-yl)methanamine hydrochloride (26.8 mg, 0.146mmol), N-ethyl-N-isopropylpropan-2-amine (32.4 μl, 0.186 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg,0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) atambient temperature. After 16 hours, the reaction was applied directlyto a silica gel column and eluted with a gradient (20% to 80%) of ethylacetate-hexanes to provide the title compound (67 mg, 0.132 mmol, 99.8%yield) as a white solid.

Steps B and C: Prepared according to Example 110, Steps B and C toprovide 63 mg (100%) of the title compound as a solid. MS (apci)m/z=478.1 (M+2H—Na).

EXAMPLE 112 Sodium6-chloro-7-(4-(2-(p-tolylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 110, replacing1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in Step Awith 2-(p-tolylthio)ethanamine to provide the title compound (71 mg,0.14 mmol, 99% yield) as a solid. MS (apci) m/z=497.9 (M+2H—Na).

EXAMPLE 113 Sodium6-chloro-7-(4-(2-(4-chlorophenylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl 6-chloro-7-(4-(2-(4-chlorophenylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according toExample 111, Step A, replacing (2,3-dihydro-1H-inden-2-yl)methanaminehydrochloride with 2-(4-chlorophenylthio)ethanamine hydrochloride toprovide the title compound (47 mg, 65% yield) as a solid.

Steps B and C: Followed the procedure of Example 110, Steps B and C, toprovide the title compound (44 mg, 100% yield) as a solid. MS (apci)m/z=517.8 (M+2H—Na).

EXAMPLE 114 Sodium6-chloro-7-(4-(2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 110, replacing2-(benzo[d][1,3]dioxol-5-yl)ethanamine in Step A with2-(2-ethoxyphenyl)ethanamine to provide the title compound (66 mg, 100%yield) as a solid. MS (apci) m/z=495.9 (M+2H—Na).

EXAMPLE 115 Sodium6-chloro-7-(4-(2-(2-chlorophenoxy)ethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 110, replacing2-(benzo[d][1,3]dioxol-5-yl)ethanamine in Step A with2-(2-chlorophenoxy)ethylamine to provide the title compound (69 mg, 100%yield) as a solid. MS (apci) m/z=501.9 (M+2H—Na).

EXAMPLE 116 Sodium7-(4-(2-tert-butoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Step A: Preparation of tert-butoxy-2-(2-nitrovinyl)benzene:2-tert-Butoxybenzaldehyde (550 mg, 3.09 mmol) was treated withnitromethane (1167 μL, 21.6 mmol) at ambient temperature in a flask.Solid methylamine hydrochloride (133 mg, 1.98 mmol) and sodium acetate(162 mg, 1.98 mmol) were added and the colorless reaction mixture wasstirred rapidly at ambient temperature. After 30 minutes, the reactionmixture started to turn yellow. After 16 hours, the reaction was veryyellow and precipitate has formed. Water (20 ml) and dichloromethane (40ml) were added and the layers partitioned. The dichloromethane layer wasdried with sodium sulfate, filtered, and concentrated to provide thetitle compound (705 mg, 3.19 mmol, 103% yield) as a yellow oil.

Step B: Preparation of 2-(2-tert-butoxyphenyl)ethanamine:1-tert-Butoxy-2-(2-nitrovinyl)benzene (685 mg, 3.10 mmol) intetrahydrofuran (10 ml) was cooled to 0° C. under an argon atmosphere(balloon). Lithium aluminum hydride (1 M in THF) (12384 μL, 12.4 mmol,equivalent to 470 mg) was added dropwise over 5 minutes. The reactionwas stirred at 0° C. for 30 minutes and then at ambient temperature 4hours. The reaction was quenched with 0.470 ml water at 0° C., followedby 0.470 ml 1 N aqueous NaOH at 0° C. After 15 minutes, an additional1.45 ml water was added and the reaction mixture was warmed to ambienttemperature and stirred rapidly for 1 hour, after which ethyl acetate(20 ml) and potassium were added. The reaction mixture was filtered andwashed with ethyl acetate. The combined filtrate was concentrated invacuo to afford the title compound (575 mg, 2.97 mmol, 96.1% yield) as ayellow oil.

Steps C-E: Followed the procedures of Example 110, Steps A-C to providethe title compound (59 mg, 99%) as a solid. MS (apci) m/z=523.7(M+2H—Na).

EXAMPLE 117 Sodium6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of methyl(2-(2-nitrovinyl)phenyl): Preparedaccording to Example 116, Step A, replacing the aldehyde with2-(methylthio)benzaldehyde. The crude reaction was purified on silicagel (elution with a gradient of 5-20% ethyl acetate-hexanes) to providethe title compound (319 mg, 48% yield) as a solid.

Step B: Preparation of 2-(2-(methylthio)phenyl)ethanamine: Preparedaccording to Example 116, Step A, replacing1-tert-butoxy-2-(2-nitrovinyl)benzene with(E)-methyl(2-(2-nitrovinyl)phenyl)sulfane to afford the title compound(278 mg, 102% yield) as an oil.

Step C: Preparation of ethyl 6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according toExample 110, Step A, replacing 2-(benzo[d][1,3]dioxol-5-yl)ethanaminewith 2-(2-(methylthio) phenyl)ethanamine to provide the title compound(58 mg, 83%) as a solid.

Step D: Preparation of 6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Prepared accordingto Example 110, Step B to provide the title compound (53 mg, 100%) as asolid.

Step E: Preparation sodium 6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according toExample 110, Step C to provide the title compound (55 mg, 99%) as asolid. MS (apci) m/z=497.9 (M+2H—Na).

EXAMPLE 118 Sodium6-chloro-7-(4-(4-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of methyl(4-(2-nitrovinyl)phenyl)sulfane: Preparedaccording to Example 116, Step A, replacing 2-tert-butoxybenzaldehydewith 4-(methylthio)benzaldehyde and the crude product was crystallizedfrom methanol to provide the title compound (85 mg, 12% yield) as asolid.

Step B: Preparation of 2-(4-(methylthio)phenyl)ethanamine: Preparedaccording to Example 116, Step B, replacing1-tert-Butoxy-2-(2-nitrovinyl)benzene withmethyl(4-(2-nitrovinyl)phenyl)sulfane to afford the title compound (64mg, 98% yield) as an oil.

Step C: Preparation of ethyl6-chloro-7-(4-(4-(methylthio)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to Example 110, Step A, replacing2-(benzo[d][1,3]dioxol-5-yl)ethanamine with2-(4-(methylthio)phenyl)ethanamine to provide the title compound (59 mg,56%) as a solid.

Step D: Preparation of6-chloro-7-(4-(4-(methylthio)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylicacid: Prepared according to Example 110, Step B, to provide the titlecompound (59 mg, 100%) as a solid.

Step E: Preparation sodium sodium6-chloro-7-(4-(4-(methylthio)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to Example 110, Step C, to provide the title compound(57 mg, 99%) as a solid. MS (apci) m/z=497.9 (M+2H—Na).

EXAMPLE 119 Sodium6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of tert-butyl1-(3-chlorophenyl)pyrrolidin-3-ylcarbamate: 3-N-Boc-amino pyrrolidine(120 mg, 0.644 mmol), cesium carbonate (252 mg, 0.773 mmol), and3-bromochlorobenzene (75.7 μl, 0.644 mmol) were suspended in drytoluene. Argon was bubbled through the suspension for 2 minutes and thentris(dibenyzlideneacetone)dipalladium (35.4 mg, 0.0387 mmol) andrac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (60.4 mg, 0.0966 mmol)were added. The reaction vial was capped and heated to 110° C. withrapid stirring. After 15 hours, reaction was cooled to ambienttemperature and applied directly to a silica gel column. Elution was agradient of 5-70% ethyl acetate-hexanes provided the title compound (120mg, 0.404 mmol, 62.8% yield) as an oil.

Step B: Preparation of 1-(3-chlorophenyl)pyrrolidin-3-aminedihydrochloride: tert-Butyl 1-(3-chlorophenyl)pyrrolidin-3-ylcarbamate(120 mg, 0.404 mmol) in dichloromethane (0.5 ml) was treated with 4molar hydrogen chloride in dioxane (1011 μL, 4.04 mmol) at ambienttemperature in an open flask with rapid stirring. After 4 hours, thereaction was concentrated in vacuo to provide the di-hydrochloride saltof the title compound as a crude solid (122 mg, >100%).

Step C: Preparation of ethyl6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate:Crude 1-(3-chlorophenyl)pyrrolidin-3-amine dihydrochloride (53.7 mg,0.199 mmol) in dichloromethane was treated sequentially withN-ethyl-N-isopropylpropan-2-amine (78.6 μl, 0.451 mmol),4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (50 mg, 0.133 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg,0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) atambient temperature. After 5 hours, the reaction was applied directly toa silica gel column. Elution with a gradient of 20-70% ethylacetate-hexanes provided the title compound (70 mg, 0.126 mmol, 95.0%yield) as a solid.

Step D: Preparation of6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Prepared according to Example 110, Step B to provide the titlecompound (65 mg, 99%) as a solid.

Step E: Preparation of sodium6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to Example 110, Step C to provide the title compound(66 mg, 97%) as a solid. MS (apci) m/z=526.9 (M+2H—Na).

EXAMPLE 120 Sodium6-chloro-7-(4-(1-(3-chlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 119, replacing 3-N-Boc-amino pyrrolidinein Step A with 4-(N-Boc-amino)-piperidine to provide the title compound(59 mg, 99%) as a solid. MS (apci) m/z=541.0 (M+2H—Na).

EXAMPLE 121 Sodium6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)azetidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 119, replacing 3-N-Boc-amino pyrrolidinein Step A with azetidin-3-yl-carbamic acid to provide the title compound(28 mg, 96%) as a solid. MS (apci) m/z=547.0 (M+2H—Na).

EXAMPLE 122 Sodium6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 119, replacing 3-bromochlorobenzene inStep A with 1-bromo-3-(trifluoromethyl)benzene to provide the titlecompound (70 mg, 99%) as a solid. MS (apci) m/z=560.9 (M+2H—Na).

EXAMPLE 123 Sodium6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 119, replacing 3-N-Boc-amino pyrrolidinein Step A with 4-(N-Boc-amino)-piperidine and replacing3-bromochlorobenzene with 1-bromo-3-(trifluoromethyl)benzene to providethe title compound (65 mg, 98%) as a solid. MS (apci) m/z=575.0(M+2H—Na).

EXAMPLE 124 Sodium6-chloro-7-(4-(1-(2,4-dichlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 119, replacing 3-N-Boc-amino pyrrolidinewith 4-(N—BOC amino)-piperidine and replacing 3-bromochlorobenzene with1-bromo-2,4-dichlorobenzene in Step A to provide the title compound (47mg, 100%) as a solid. MS (apci) m/z=574.9 (M+2H—Na).

EXAMPLE 125 Sodium6-chloro-7-(4-((S)-1-(3-chlorophenyl)piperidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 119, replacing 3-N-Boc-amino pyrrolidinein Step A with (S)-tert-butyl piperidin-3-ylcarbamate to provide thetitle compound (70 mg, 100%) as a solid. MS (apci) m/z=541.0 (M+2H—Na).

EXAMPLE 1266-Cyano-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation methyl6-cyano-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to Example 111, Step A replacing4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid with4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid to providethe title compound (74 mg, 99% yield) as a solid.

Step B: Preparation of6-cyano-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Prepared according to Example 110, Step B to provide the titlecompound (61 mg, 85%) as a solid. MS (apci) m/z=469.1 (M+H).

EXAMPLE 1277-(4-(4-tert-Butylcyclohexylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Step A: Preparation methyl7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate:Prepared according to Example 110, Step A where the reacting carboxylicacid replacing 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid with 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid andreplacing 2-(benzo[d][1,3]dioxol-5-yl)ethanamine with4-tert-Butylcyclohexylamine to provide the title compound (73 mg, 97%yield) as a solid.

Step B: Preparation of7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid: Prepared according to Example 110, Step B to provide the titlecompound (68 mg, 91%) as a solid. MS (apci) m/z=477.2 (M+H).

EXAMPLE 128 7-(4-(4-Chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of 7-methoxy-2,3-dihydrochromen-4-one:7-Hydroxy-2,3-dihydrochromen-4-one (4.47 g, 27.2 mmol) was diluted withtetrahydrofuran (40 mL) followed by the addition of K₂CO₃ (5.64 g, 40.8mmol) and MeI (2.55 mL, 40.8 mmol). The reaction was heated at 70° C.for 5 hours. The reaction was allowed to cool and loaded onto a Biotage40M cartridge running a gradient 5% ethyl acetate/hexanes to 75% toyield the title compound (3.5 g, 72.1% yield).

Step B: Preparation of7-methoxy-4-(trimethylsilyloxy)-3,4-dihydro-2H-chromene-4-carbonitrile:To a thick suspension of 7-methoxy-2,3-dihydrochromen-4-one (1.04 g,5.84 mmol) in tetrahydrofuran (5 mL) was added zinc(II) iodide (0.0932g, 0.292 mmol) followed by the dropwise addition of(trimethylsilyl)formonitrile (2.35 mL, 17.5 mmol). The reaction wasstirred at ambient temperature for 4 hours, then diluted with ethylacetate (50 mL) and washed with water (50 mL) and brine (50 mL). Thecombined organic layers were dried over magnesium sulfate andconcentrated to give the title compound (1.62 g, 100% yield) which wasused directly in the next step with further purification.

Step C: Preparation of 7-methoxy-3,4-dihydro-2H-chromene-4-carboxylicacid7-methoxy-4-(trimethylsilyloxy)-3,4-dihydro-2H-chromene-4-carbonitrile:To 7-methoxy-4-(trimethylsilyloxy)chroman-4-carbonitrile (1.62 g, 5.84mmol) in acetic acid (15 mL) and HCl (15 mL) was added SnCl₂ dihydrate(5.27 g, 23.4 mmol). The reaction was heated at 130° C. for 1 day. Thereaction was cooled, diluted with dichloromethane (50 mL) and washedwith water (50 mL) and brine (50 mL). The combined organic layers weredried over magnesium sulfate and concentrated. The residue waschromatographed over silica gel using a gradient of 0.5% MeOH/CH₂Cl₂containing 0.5% acetic acid to 10% MeOH/CH₂Cl₂ containing 0.5% aceticacid to provide the title compound (0.95 g, 78.1% yield).

Step D: Preparation of methyl7-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate: To7-methoxy-3,4-dihydro-2H-chromene-4-carboxylic acid (0.71 g, 3.41 mmol)was added HBr (0.276 g, 3.41 mmol) and the reaction was heated at 130°C. for 3 hours. The reaction was cooled and concentrated, and theresidue was loaded onto a silica gel samplet. The product was elutedusing a gradient of 0.5% MeOH/CH₂Cl₂ containing 0.5% acetic acid to 10%acetic acid/CH₂Cl₂ containing 0.5% acetic acid. The isolated product wasdissolved in MeOH (5 mL) and concentrated sulfuric acid (1 mL) was addedand the reaction heated at 75° C. After 2 hours, reaction was cooled,diluted with ethyl acetate (25 mL) and washed with water (25 mL) andbrine (25 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by silica gel chromatography,eluting with a gradient of 0.5% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂, toprovide the title compound (0.312 g, 43.9% yield).

Step E: Preparation of7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3,4-dihydro-2H-chromene-4-carboxylicacid: Methyl 7-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate (0.075 g,0.360 mmol), N-(4-chlorophenethyl)-4-iodobenzamide (0.126 g, 0.327mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.00603 g, 0.0327 mmol),CuCl (0.0162 g, 0.164 mmol) and Cs₂CO₃ (0.213 g, 0.655 mmol) werestirred together in N-methylpyrrolidone (2 mL) at 120° C. for 3 hours.The reaction was cooled and loaded onto a silica gel samplet. Theproduct was a eluted over using a gradient of 5% ethyl acetate/hexanesto 75% ethyl acetate/hexanes to provide the title compound (0.056 g,37.8% yield).

Step F: Preparation of7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3,4-dihydro-2H-chromene-4-carboxylicacid: Methyl7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3,4-dihydro-2H-chromene-4-carboxylatewas dissolved in THF (3 mL) and methanol (3 mL) and treated with 1N NaOH(3 mL), and the reaction was stirred for 1 hour. The reaction wasdiluted with CH₂Cl₂ (25 mL) and washed with 2N HCl (25 mL), dried overmagnesium sulfate and concentrated. The residue was purified by silicagel chromatography, eluting with a gradient of 0.5% MeOH/CH₂Cl₂containing 0.5% acetic acid to 7.5% MeOH/CH₂Cl₂ containing 0.5% aceticacid to provide the title compound (0.056 g, 37.8% yield) as a whitesolid. MS (ESI)=452.1 (M+1).

EXAMPLE 1297-(4-(4-Chlorophenethylcarbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylicacid

Step A: Preparation of7-fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile:7-Fluoro-2,3-dihydrochromen-4-one (470 mg, 2.829 mmol) and ZnI₂ (45.15mg, 0.1414 mmol) was diluted with trimethylsilyl cyanide (1.413 mL,11.32 mmol). The reaction was stirred for 4 hours at ambienttemperature. The reaction was diluted with CH₂Cl₂ and washed withsaturated sodium bicarbonate twice. The organic layer was dried overMgSO₄, filtered and concentrated to yield the title compound (750 mg,99.92% yield).

Step B: Preparation of 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylicacid: 7-Fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile (750 mg, 2.83mmol) and SnCl₂ dihydrate (2551 mg, 11.3 mmol) were diluted with glacialacetic acid (3 mL) and concentrated HCl (3 mL). The reaction was heatedin an oil bath at 130° C. and stirred overnight. The reaction wasallowed to cool, diluted with water and ethyl acetate. The layers wereseparated and the organic layer was dried over MgSO₄, filtered andconcentrated to yield the title compound (465 mg, 83.9% yield).

Step C: Preparation of methyl7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate:7-Fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid (346 mg, 1.76 mmol)was diluted with (THF) 2 mL, methanol (2 mL) and 4 drops of sulfuricacid. The reaction was heated at 55° C. and stirred for 12 hours. Thereaction was cooled to ambient temperature, diluted with ethyl acetateand saturated sodium bicarbonate. The layers were separated and theorganic layer was dried over MgSO₄, filtered and concentrated to yieldthe title compound (366 mg, 98.7% yield).

Step D: Preparation of methyl6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate: Methyl7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (336 mg, 1.60 mmol) wasdiluted with DMF (5 mL) followed by the addition of N-bromosuccinimide(313 mg, 1.76 mmol). The reaction was heated at 50° C. and stirred for2.5 hours. The reaction was cooled, diluted with ethyl acetate andwashed with water, saturated sodium bicarbonate, water, and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated. Thematerial was purified using a Biotage 40M cartridge, gradient 5% ethylacetate/hexane to 50% to yield the title compound (415 mg, 89.8% yield).

Step E: Preparation of methyl 6-cyano-7-fluorochroman-4-carboxylate:Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg,1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by theaddition of Cu(I)CN (643 mg, 7.18 mmol). The reaction was bubbled withargon for 20 minutes, then heated at 160° C. under a slight argon bubblefor 6 hours. The reaction was cooled to ambient temperature and loadeddirectly onto a Biotage 25 column eluting with 5% ethyl acetate/hexanesto 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).

Step F: Preparation of4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)-3-methylbenzoic acid: Amixture of K₂CO₃ (0.026 g, 0.19 mmol), methyl6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (0.040 g, 0.17mmol), and tert-butyl 4-hydroxy-3-methylbenzoate (0.039 g, 0.19 mmol) in0.5 ml NMP was heated under argon at 120° C. for 24 hours. The reactionwas cooled, poured into 10% aqueous HCl, and extracted with ethylacetate. The organic extracts were dried with sodium sulfate andpurified on silica gel. Elution with 25% ethyl acetate-hexanes providedmaterial that still contained impurities. The mixture was deprotetctedwith to 1:1 trifluoracetic acid-dichloromethane to provide the titlecompound (13 mg, still impure) which was used directly in the next step.

Step G: Preparation of methyl7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylate:4-(6-Cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)-3-methylbenzoicacid (0.013 g, 0.03539 mmol) in 1 ml dry DMF was treated withN-ethyl-N-isopropylpropan-2-amine (0.01233 ml, 0.07078 mmol), HBTU(0.01610 g, 0.04247 mmol) and 2-(4-chlorophenyl)ethanamine (0.009843 ml,0.07078 mmol) at ambient temperature. After 48 h, the reaction waspoured into 10% aqueous HCl, extracted with ethyl acetate, dried oversodium sulfate, filtered, and concentrated to provide the crude materialas a yellow film. Purification of the crude material on silica gel,eluting with 1% MeOH/DCM, provided the title compound (6 mg, 34%)

Step H: Preparation of7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylicacid: Methyl7-(4-((4-chlorophenethyl)carbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylate(0.0063 g, 0.0125 mmol) was taken up in 0.5 ml THF and treated withaqueous 1.0 molar LiOH (0.0250 ml, 0.0250 mmol) at ambient temperature.After 48 hours, the reaction was neutralized with acetic acid andconcentrated in vacuo. Purification of the crude material by preparativethin layer chromatography using 5% MeOH/DCM with 1% HOAc as the mobilephase provided the title compound (2 mg, 38%). MS (apci) m/z=491.1(M+H).

EXAMPLE 1306-Cyano-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Methyl 6-cyano-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.030 g,0.0849 mmol) in 2 ml dry dichloromethane was treated with oxalylchloride (0.0296 ml, 0.340 mmol) followed by 1 drop DMF at ambienttemperature. After 45 minutes, the solution was concentrated undervacuum and the residue re-suspended in 2 ml DCM and treated with(R)-2-phenylpropan-1-amine (0.0182 ml, 0.127 mmol),4-dimethylaminopyridine (0.00104 g, 0.00849 mmol), and pyridine (0.978)(0.0137 ml, 0.170 mmol). After 12 hours, the reaction was diluted withdichloromethane and washed with 10% aqueous HCl. The dichloromethanelayer was dried over sodium sulfate, filtered, concentrated, andpurified on silica gel. Elution with a gradient of 30-50% ethylacetate-hexanes provided the title compound (39 mg, 98%) as a solid.

Step B:6-Cyano-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Prepared according to Example 129, Step H to provide the titlecompound (13 mg, 27%) as an oil. MS (ESI) m/z=457.1 (M+H).

EXAMPLE 1316-Cyano-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 130 step A replacing(R)-2-phenylpropan-1-amine with (S)-2-phenylpropan-1-amine to providethe title compound (12 mg, 35%) as a solid. MS (ESI) m/z=457.1 (M+H).

EXAMPLE 1327-(4-(1-(4-Chlorophenyl)propan-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Prepared according to Example 130, step A, replacing(R)-2-phenylpropan-1-amine with 1-(4-chlorophenyl)propan-2-aminehydrochloride to provide the title compound (5 mg, 29%) as a solid. MS(ESI) m/z=491.0 (M+H).

EXAMPLE 1337-(4-(4-Chloro-3-methoxyphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Prepared according to Example 130, step A replacing(R)-2-phenylpropan-1-amine with 2-(4-chloro-3-methoxyphenyl)ethanamineto provide the title compound (12 mg, 50%). MS (ESI) m/z=507.0 (M+H).

EXAMPLE 1347-(4-(3-tert-Butylphenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid

Step A: Methyl7-(4-(3-tert-butylphenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate:4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (90 mg, 0.255mmol), 3-tert-butylaniline (38 mg, 0.255 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg,0.280 mmol), and 1-hydroxy-7-azabenzotriazole (25 mg, 0.255 mmol) werecombined in a round bottom flask and taken up in 5 ml dry of DMF. Thereaction was stirred at ambient temperature for 12 hours and then pouredinto 10% HCl and extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, filtered, concentrated, and purified onsilica gel. Elution with a gradient of 2-5% methanol-dichloromethaneprovided the title compound (100 mg, 81%).

Step B:7-(4-(3-tert-butylphenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid: Prepared according to Example 129, Step H to provide the titlecompound (46 mg, 47%) as solid. MS (apci) m/z=468.8 (M−H).

EXAMPLE 1356-Cyano-7-(4-(3-isopropoxyphenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to Example 134, step A replacing 3-tert-butylanilinewith 3-isopropoxyaniline to provide the title compound (53 mg, 56%) as asolid. MS (apci) m/z=473.1 (M+H).

EXAMPLE 136 Sodium6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (51.5 mg, 0.137 mmol), in 1:1 DMF:DCM (0.1 M) wassequentially treated with 3,4-dichlorobenzylamine (26.5 mg, 0.150 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.4 mg,0.164 mmol), and 1-Hydroxy-7-azabenzotriazole (5.58 mg, 0.0410 mmol) atambient temperature. After 16 hours the reaction was applied directly toa silica gel column and eluted with a gradient (15% to 60%) of ethylacetate-hexanes to provide the title compound (69.0 mg, 0.129 mmol,94.4% yield) as a white solid.

Step B: Preparation of6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylicacid: ethyl6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate(69.0 mg, 0.129 mmol) was reacted with 1.0 molar sodium hydroxide (516μL, 0.516 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hoursthe reaction was diluted with ethyl acetate, neutralized with 1.0 molarhydrochloric acid (542 μL, 0.542 mmol) and partitioned between saturatedaqueous sodium chloride The organic layer was dried with sodium sulfate,filtered, concentrated, and dried under high vacuum to provide the titlecompound (49.4 mg, 0.0975 mmol, 75.6% yield) as a solid.

Step C: Preparation of sodium6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate:6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy) chroman-4-carboxylicacid (49.4 mg, 0.0975 mmol), 0.1 molar in tetrahydrofuran, was treatedwith sodium methanolate (195 μL, 0.0975 mmol) at ambient temperature.After 20 minutes, the solvent was removed in vacuo. The resulting solidwas taken up in ethyl acetate and concentrated in vacuo. The solid wastaken up in 4:1 dichloromethane-hexanes and concentrated in vacuo anddried under high vacuum to provide sodium6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylate(51.5 mg, 0.0974 mmol, 99.9% yield) as a solid. MS (apci) m/z=507.6(M+2H—Na).

EXAMPLE 137 Sodium6-chloro-7-(4-(4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting2-(4-Trifluoromethyl-phenyl)-ethylamine for 3,4-dichlorobenzylamine toprovide sodium6-chloro-7-(4-(4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(45.0 mg, 0.0830 mmol, 94.5% yield) as a solid. MS (apci) m/z=518.9(M+2H—Na).

EXAMPLE 138 Sodium6-chloro-7-(4-(3,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting3,4-Dichlorophenethylamine for 3,4-dichlorobenzylamine to provide sodium6-chloro-7-(4-(3,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(81.1 mg, 0.149 mmol, 99.6% yield) as a solid. MS (apci) m/z=522.0(M+2H—Na).

EXAMPLE 139 Sodium6-chloro-7-(4-(2,3-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting2-(2,3-dichlorophenyl)ethanamine for 3,4-dichlorobenzylamine to providesodium6-chloro-7-(4-(2,3-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(43.0 mg, 0.0792 mmol, 100% yield) as a solid. MS (apci) m/z=520.0(M+2H—Na).

EXAMPLE 140 Sodium6-chloro-7-(4-(4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting 4-methoxyphenethylaminefor 3,4-dichlorobenzylamine to provide sodium6-chloro-7-(4-(4-methoxyphenethyl-carbamoyl)\phenoxy)chroman-4-carboxylate(49.0 mg, 0.0972 mmol, 99.3% yield) as a solid. MS (apci) m/z=482.0(M+2H—Na).

EXAMPLE 141 Sodium6-chloro-7-(4-(3,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting3,4-dimethoxyphenethylamine for 3,4-dichlorobenzylamine to providesodium6-chloro-7-(4-(3,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(52.0 mg, 0.0974 mmol, 99.1% yield) as a solid. MS (apci) m/z=511.9(M+2H—Na).

EXAMPLE 142 Sodium7-(4-(4-tert-butylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Prepared according to Example 136, substituting2(-4-tert-butylphenyl)ethylamine for 3,4-dichlorobenzylamine to providesodium7-(4-(4-tert-butylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(36.0 mg, 0.0679 mmol, 97.5% yield) as a solid. MS (apci) m/z=508.0(M+2H—Na).

EXAMPLE 143 Sodium6-chloro-7-(4-(3-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting 3-methoxyphenethylaminefor 3,4-dichlorobenzylamine to provide sodium6-chloro-7-(4-(3-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(54.0 mg, 0.107 mmol, 98.9% yield) as a solid. MS (apci) m/z=481.9(M+2H—Na).

EXAMPLE 144 Sodium6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting2-(2,4-dimethoxyphenyl)ethanamine for 3,4-dichlorobenzylamine to providesodium6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(34.0 mg, 0.0637 mmol, 99.1% yield) as a solid. MS (apci) m/z=511.9(M+2H—Na).

EXAMPLE 145 Sodium6-chloro-7-(4-(3-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting 3-fluorophenethylaminefor 3,4-dichlorobenzylamine to provide sodium6-chloro-7-(4-(3-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(49.7 mg, 0.0996 mmol, 98.5% yield) as a solid. MS (apci) m/z=470.0(M+2H—Na).

EXAMPLE 146 Sodium6-chloro-7-(4-(3-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 136, substituting 3-Methylphenethylaminefor 3,4-dichlorobenzylamine to provide sodium6-chloro-7-(4-(3-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(49.0 mg, 0.100 mmol, 99.8% yield) as a solid. MS (apci) m/z=466.0(M+2H—Na).

EXAMPLE 147 Sodium6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 2-(4-(trifluoromethylthio)phenyl)ethanamine:4-(Trifluoromethylthio)phenylacetonitrile (183.4 mg, 0.844 mmol), 0.3molar in THF, was heated to reflux and then treated with Borane-methylsulfide complex (88.09 μL, 0.929 mmol). After 1 hour of refluxing, thereaction mixture was cooled to ambient temperature and then treateddropwise with 5.0 molar hydrochloric acid (607.9 μL, 3.040 mmol). Thereaction mixture was then heated to reflux for an additional 30 minutes.After 30 minutes the reaction mixture was cooled to 0° C. and thentreated with 1.0 molar sodium hydroxide (4644 μL, 4.644 mmol). Thereaction mixture was diluted with diethyl ether and partitioned withdeionized water. The organic layer was dried with potassium carbonate98% powder, filtered, concentrated, and dried for one minute under highvacuum to provide the title compound (170.7 mg, 0.772 mmol, 91.2% yield)as a light yellow oil.

Step B: Preparation of ethyl 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid(Preparation 1) (50.7 mg, 0.137 mmol), in 1:1 DCM:DMF (0.1 M) wassequentially treated with 2-(4-(trifluoromethylthio)phenyl)ethanamine(32.7 mg, 0.148 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (31.0 mg, 0.161 mmol), 1-hydroxy-7-azabenzotriazole (5.49mg, 0.0404 mmol), and N,N-Diisopropylethylamine (26.1 mg, 0.202 mmol) atambient temperature. After 16 hours the reaction was applied directly toa silica gel column and eluted with a gradient (15% to 60%) of ethylacetate-hexanes to provide the title compound (73.3 mg, 0.126 mmol,93.9% yield) as a white solid.

Step C: Preparation of 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid: ethyl6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(73.3 mg, 0.126 mmol) was reacted with 1.0 molar sodium hydroxide (506μL, 0.506 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hoursthe reaction was diluted with ethyl acetate, neutralized with 1.0 molarhydrochloric acid (531 μL, 0.531 mmol) and partitioned between saturatedaqueous sodium chloride. The organic layer was dried with sodiumsulfate, filtered, concentrated, and dried under high vacuum to providethe title compound (58.7 mg, 0.106 mmol, 84.2% yield) as a solid.

Step D: Preparation of sodium 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:6-Chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (58.7 mg, 0.106mmol), 0.1 molar in tetrahydrofuran, was treated with sodium methanolate(213 μL, 0.106 mmol) at ambient temperature. After 20 minutes, thesolvent was removed in vacuo. The resulting solid was taken up in ethylacetate and concentrated in vacuo. The solid was taken up in 4:1dichloromethane-hexanes and concentrated in vacuo and dried under highvacuum to provide sodium6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(60.0 mg, 0.105 mmol, 98.3% yield) as a solid. MS (apci) m/z=552.0(M+2H—Na).

EXAMPLE 148 Sodium6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 2-(3,5-dichlorophenyl)acetonitrile:3,5-Dichlorobenzyl chloride (315.6 mg, 1.615 mmol), 0.2 molar in DMSO,was treated with sodium cyanide (158.2 mg, 3.229 mmol) and allowed tostir at ambient temperature for 24 hours. After 24 hours the reactionmixture was diluted with diethyl ether and partitioned between saturatedaqueous sodium chloride. The organic layer was dried with magnesiumsulfate, filtered, and concentrated to provide the title compound (155.5mg, 0.836 mmol, 51.8% yield) as a dark red oil.

Step B: Preparation of 2-(3,5-dichlorophenyl)ethanamine:2-(3,5-dichlorophenyl)acetonitrile (155.5 mg, 0.836 mmol), 0.3 molar inTHF, was heated to reflux and then treated with Borane-methyl sulfidecomplex (87.20 μL, 0.919 mmol). After 1 hour of refluxing, the reactionmixture was cooled to ambient temperature and then treated dropwise with5.0 molar hydrochloric acid (601.8 μl, 3.009 mmol). The reaction mixturewas heated to reflux for an additional 30 minutes. After 30 minutes thereaction mixture was cooled to 0° C. and treated with 1.0 molar sodiumhydroxide (4597 μL, 4.597 mmol). The reaction mixture was diluted withdiethyl ether and partitioned with deionized water. The organic layerwas dried with potassium carbonate 98% powder, filtered, concentrated,and dried for one minute under high vacuum to provide the title compound(135.2 mg, 0.7113 mmol, 85.1% yield) as a light yellow oil.

Step C: Preparation of ethyl6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (54.2 mg, 0.144 mmol), in 1:1 DCM:DMF (0.1 M) wassequentially treated with 2-(3,5-dichlorophenyl)ethanamine (30.1 mg,0.158 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(33.1 mg, 0.173 mmol), 1-Hydroxy-7-azabenzotriazole (5.87 mg, 0.0432mmol), and N,N-diisopropylethylamine (27.9 mg, 0.216 mmol) at ambienttemperature. After 24 hours the reaction was applied directly to asilica gel column and eluted with a gradient (15% to 60%) of ethylacetate-hexanes to provide the title compound (76.4 mg, 0.139 mmol,96.8% yield) as a white solid.

Step D: Preparation of6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: ethyl6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(76.4 mg, 0.139 mmol) was reacted with 1.0 molar sodium hydroxide (557μl, 0.557 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hoursthe reaction was diluted with ethyl acetate, neutralized with 1.0 molarhydrochloric acid (585 μl, 0.585 mmol) and partitioned between saturatedaqueous sodium chloride. The organic layer was dried with sodiumsulfate, filtered, concentrated, and dried under high vacuum to providethe title compound (72.5 mg, 0.115 mmol, 82.8% yield) as a solid.

Step E: Preparation of sodium6-chloro-7-(4-(3,5-dichlorophenethyl-carbamoyl)phenoxy)chroman-4-carboxylate:6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (60.0 mg, 0.115 mmol), 0.1 molar in tetrahydrofuran, was treatedwith sodium methanolate (230 μl, 0.115 mmol) at ambient temperature.After 20 minutes, the solvent was removed in vacuo. The resulting solidwas taken up in ethyl acetate and concentrated in vacuo. The solid wastaken up in 4:1 dichloromethane-hexanes and concentrated in vacuo anddried under high vacuum to provide sodium6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(62.0 mg, 0.114 mmol, 99.1% yield) as a solid. MS (apci) m/z=521.9(M+2H—Na)

EXAMPLE 149

Sodium6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (51.6 mg, 0.137 mmol), in 1:1 DCM:DMF (0.1 M) wassequentially treated with 3-phenoxyphenethylamine (32.1 mg, 0.151 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.5 mg,0.164 mmol), and 1-hydroxy-7-azabenzotriazole (5.59 mg, 0.0411 mmol) atambient temperature. After 24 hours the reaction was applied directly toa silica gel column and eluted with a gradient (15% to 60%) of ethylacetate-hexanes to provide the title compound (71.6 mg, 0.125 mmol,91.4% yield) as a white solid.

Step B: Preparation of6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Ethyl6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(71.6 mg, 0.125 mmol) was reacted with 1.0 molar sodium hydroxide (501μl, 0.501 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hoursthe reaction was diluted with ethyl acetate, neutralized with 1.0 molarhydrochloric acid (526 μl, 0.526 mmol) and partitioned between saturatedaqueous sodium chloride. The organic layer was dried with sodiumsulfate, filtered, concentrated, and dried under high vacuum to providethe title compound (56.4 mg, 0.104 mmol, 82.8% yield) as a solid.

Step C: Preparation of sodium6-chloro-7-(4-(3-phenoxyphenethyl-carbamoyl)phenoxy)chroman-4-carboxylate:6-Chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (56.4 mg, 0.104 mmol), 0.1 molar in tetrahydrofuran, was treatedwith sodium methanolate (207 μl, 0.104 mmol) at ambient temperature.After 20 minutes, the solvent was removed in vacuo. The resulting solidwas taken up in ethyl acetate and concentrated in vacuo. The solid wastaken up in 4:1 dichloromethane-hexanes and concentrated in vacuo anddried under high vacuum to provide sodium6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(58.0 mg, 0.102 mmol, 98.8% yield) as a solid. MS (apci) m/z=543.9(M+2H—Na).

EXAMPLE 150 Sodium6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1) (48.8 mg, 0.130 mmol), in 1:1 DCM:DMF (0.1 M) wassequentially treated with 2-(3-chlorophenyl)ethylamine (22.2 mg, 0.143mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.8mg, 0.155 mmol), and 1-hydroxy-7-azabenzotriazole (5.29 mg, 0.0389 mmol)at ambient temperature. After 48 hours the reaction was applied directlyto a silica gel column and eluted with a gradient (15% to 60%) of ethylacetate-hexanes to provide the title compound (61.1 mg, 0.119 mmol,91.7% yield) as a white solid.

Step B: Preparation of sodium6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:ethyl6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(61.1 mg, 0.119 mmol) was reacted with 1.0 molar sodium hydroxide (475μl, 0.475 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hoursthe reaction was diluted with ethyl acetate, neutralized with 1.0 molarhydrochloric acid (499 μL, 0.499 mmol) and partitioned between saturatedaqueous sodium chloride. The organic layer was dried with sodiumsulfate, filtered, concentrated, and dried under high vacuum to providethe title compound (40.2 mg, 0.0827 mmol, 69.6% yield) as a solid.

Step C: Preparation of sodium6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate:6-Chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy) chroman-4-carboxylicacid (40.2 mg, 0.0827 mmol), 0.1 molar in tetrahydrofuran, was treatedwith sodium methanolate (165 μL, 0.0827 mmol) at ambient temperature.After 20 minutes, the solvent was removed in vacuo. The resulting solidwas taken up in ethyl acetate and concentrated in vacuo. The solid wastaken up in 4:1 dichloromethane-hexanes and concentrated in vacuo anddried under high vacuum to provide sodium6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(42.0 mg, 0.0826 mmol, 100% yield) as a solid. MS (apci) m/z=486.0(M+2H—Na).

EXAMPLE 151 Sodium6-chloro-7-(4-(3-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(3-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:Prepared according to Example 150, substituting2-(3-Trifluoromethylphenyl)-ethylamine for 2-(3-chlorophenyl)ethylamineto provide sodium6-chloro-7-(4-(3-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(54.0 mg, 0.0997 mmol, 99.0% yield) as a solid. MS (apci) m/z=517.8(M+2H−Na).

EXAMPLE 152 Sodium6-chloro-7-(4-(2-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 150, substituting2-(2-trifluoromethylphenyl)ethylamine for 2-(3-chlorophenyl)ethylamineto provide sodium6-chloro-7-(4-(2-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(55.0 mg, 0.101 mmol, 101% yield) as a solid. MS (apci) m/z=520.0(M+2H—Na).

EXAMPLE 153 Sodium6-chloro-7-(4-(2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to Example 150, substituting 2-fluorophenethylaminefor 2-(3-chlorophenyl)ethylamine to provide sodium6-chloro-7-(4-(2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate(47.0 mg, 0.0956 mmol, 100% yield) as a solid. MS (apci) m/z=470.1(M+2H—Na).

EXAMPLE 1546-Cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of methyl6-cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoicacid (0.050 g, 0.1415 mmol) in dichloromethane (0.7 ml) andN,N-dimethylformamide (1 drop) was added oxalyl dichloride (0.01358 ml,0.1557 mmol), and the reaction was stirred at ambient temperature for 30minutes. 3-(Trifluoromethyl)aniline (0.01944 ml, 0.1557 mmol) andtriethylamine (0.04339 ml, 0.3113 mmol) were added, and the reaction wasstirred at ambient temperature for 3 days. The reaction mixture wasdiluted with ethyl acetate and washed with 1M hydrochloric acid,saturated sodium bicarbonate, and saturated sodium chloride, dried overanhydrous sodium sulfate, filtered, and concentrated. The residue wasdiluted with dichloromethane and stirred with excess amine-3functionalized silica gel for 30 minutes, then filtered andconcentrated. The crude material was purified by preparative thin layerchromatography eluting with 25% EtOAc in hexanes to yield 19 mg of thetitle compound (27% yield).

Step B: Preparation of6-cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of methyl6-cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylate(0.019 g, 0.0383 mmol) in 3:1 THF/methanol (2 ml) was added 1M sodiumhydroxide (0.0459 ml, 0.0459 mmol), and the reaction was stirred atambient temperature overnight. The reaction was concentrated andpartitioned between EtOAc and diluted HCl in water. The aqueous wasextracted once with EtOAc, and the combined organic layers were driedover sodium sulfate, filtered and concentrated. The crude material waspurified by preparative thin layer chromatography eluting with 95:5:1dichloromethane/methanol/acetic acid to yield 10 mg of the titlecompound (54.2% yield). MS (apci) m/z=480.8 (M+H).

EXAMPLE 1556-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid (Mixture of cis and trans isomers)

Step A: Preparation of 4-phenylcyclohexanone oxime: To a solution of4-phenylcyclohexanone (1.50 g, 8.609 mmol) in 95% ethanol (20 ml) wasadded 50% hydroxylamine in water (5.276 ml, 86.09 mmol), and thereaction was heated to reflux for 1 hour. The reaction was allowed tocool to ambient temperature, and the product was precipitated by theslow addition of water. The solids were collected via filtration toyield 1.0 g of the title compound (61.38% yield).

Step B: Preparation of 4-phenylcyclohexanamine: To a solution of4-phenylcyclohexanone oxime (0.310 g, 1.64 mmol) in THF (3 ml) was added1M lithium aluminum hydride in THF (3.44 ml, 3.44 mmol), and thereaction was heated to reflux for 4 hours. The reaction was allowed tocool to ambient temperature, and water (0.131 ml), 1M NaOH (0.131 ml)and additional water (0.393 ml) were added, and the reaction was stirredfor 30 minutes. The reaction was diluted with EtOAc and filtered. Thefiltrate was concentrated to yield 100 mg of the title compound (34.8%yield) as a 1:1 mixture of cis and trans isomers.

Step C: Preparation of ethyl6-chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate(2 isomers): To a solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.0899 g,0.238 mmol), N,N-dimethylpyridin-4-amine (0.00291 g, 0.0238 mmol), and(1R,4R)-4-phenylcyclohexanamine (0.0627 g, 0.358 mmol) in DMF (1.25 ml)was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.0549 g, 0.286 mmol), and the reaction was stirredovernight. The reaction was diluted with EtOAc and washed with 1Mhydrochloric acid, saturated sodium bicarbonate, and saturated sodiumchloride. The organic layer was separated and dried over anhydroussodium sulfate, filtered, and concentrated. The crude material waspurified on a Biotage SP1 system eluting with a linear gradient of 5% to50% EtOAc in hexanes to yield two isomers of the product. The firsteluting isomer was collected and called isomer 1 (27 mg). The secondeluting isomer was called isomer 2 (32 mg). The relative configurationsof each of these isomers were not determined.

Step D(1): Preparation of6-chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid, isomer 1: To a solution of6-chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid, isomer 1 (0.027 g, 0.051 mmol) in 3:1 THF/methanol (1 ml) wasadded 1M sodium hydroxide (0.11 ml, 0.11 mmol), and the reaction wasstirred for 16 hours at ambient temperature. The reaction wasconcentrated, and diluted with water and 1M hydrochloric acid, andextracted twice with EtOAc. The combined organic layers were washed withsaturated sodium chloride, dried over anhydrous sodium sulfate,filtered, and concentrated to yield 26 mg of the title compound (100%yield). MS (apci) m/z=506.1 (M+H).

Step D(2): Preparation of6-chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid, isomer 2: To a solution of6-chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid, isomer 2 (0.032 g, 0.060 mmol) in 3:1 THF/methanol (1 ml) wasadded 1M sodium hydroxide (0.13 ml, 0.13 mmol), and the reaction wasstirred for 16 hours at ambient temperature. The reaction wasconcentrated, and diluted with water and 1M hydrochloric acid, andextracted twice with EtOAc. The combined organic layers were washed withsaturated sodium chloride, dried over anhydrous sodium sulfate,filtered, and concentrated to yield 30 mg of the title compound (100%yield). MS (apci) m/z=506.1 (M+H).

EXAMPLE 1567-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid

Step A: Preparation of ethyl7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid (0.154 g, 0.409 mmol), N,N-dimethylpyridin-4-amine (0.00499 g,0.0409 mmol), and 4-tert-butylcyclohexanamine (0.0875 ml, 0.490 mmol) inDMF (2 ml) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.0940 g, 0.490 mmol), and the reaction was stirred atambient temperature for 16 hours. The reaction was diluted with EtOAcand washed with 1M hydrochloric acid, saturated sodium bicarbonate, andsaturated sodium chloride. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The crude material waspurified on a Biotage SP1 system eluting with a linear gradient of 5-70%EtOAc in hexanes to yield 37 mg of the title compound (18% yield).

Step B: Preparation of7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid: To a solution of ethyl7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(0.037 g, 0.072 mmol) in 3:1 THF/methanol (1 ml) was added 1M sodiumhydroxide (0.15 ml, 0.15 mmol), and the reaction was stirred for 16hours at ambient temperature. The reaction was concentrated and theresidue was diluted with dilute hydrochloric acid and extracted twicewith EtOAc. The combined organic layers were washed with saturatedsodium chloride, dried over anhydrous sodium sulfate, filtered, andconcentrated to yield 32 mg of the title compound (91% yield). MS (apci)m/z=486.1 (M+H).

EXAMPLE 1576-Chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of 4,4-dimethylcyclohexanone oxime: To a solution of4,4-dimethylcyclohexanone (0.511 g, 4.049 mmol) in 95% ethanol (20 ml)was added 50% hydroxylamine in water (2.481 ml, 40.49 mmol), and thereaction was heated to reflux for 2 hours. The reaction was cooled toambient temperature, and the product was precipitated by the addition ofwater. The solids were collected by vacuum filtration to yield 202 mg ofthe title compound (35% yield).

Step B: Preparation of 4,4-dimethylcyclohexanamine hydrochloride: To asolution of 4,4-dimethylcyclohexanone oxime (0.204 g, 1.44 mmol) in THF(3 ml) was added 1M lithium aluminum hydride in THF (3.03 ml, 3.03mmol), and the reaction was heated to reflux for 4 hours. The reactionwas allowed to cool to ambient temperature, and water (0.115 ml), 1Msodium hydroxide (115 ml), and additional water (0.345 ml) were added.The reaction was stirred for 15 minutes and filtered. The filtrate waswashed with EtOAc, and The combined organic layers were concentrated.The crude product was treated with 5M hydrogen chloride in dioxane,allowed to stir for 10 minutes, and was concentrated to yield 60 mg ofthe title compound (25.4% yield).

Step C: Preparation of ethyl6-chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid (0.0921 g, 0.244 mmol), N,N-dimethylpyridin-4-amine (0.00299 g,0.0244 mmol), triethylamine (0.0511 ml, 0.367 mmol), and4,4-dimethylcyclohexanamine hydrochloride (0.060 g, 0.367 mmol) in DMF(1.5 ml) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.0562 g, 0.293 mmol), and the reaction was stirred for16 hours. The reaction was diluted with EtOAc and washed with 1Mhydrochloric acid, saturated sodium bicarbonate, and saturated sodiumchloride. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated. The crude material was purified on a BiotageSP 1 system eluting with a linear gradient of 5-70% EtOAc in hexanes toyield 56 mg of the title compound (47.2% yield).

Step D: Preparation of6-chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate(0.056 g, 0.12 mmol) in 3:1 THF/EtOH (1 ml) was added 1M sodiumhydroxide (0.24 ml, 0.24 mmol), and the reaction was stirred at ambienttemperature overnight. The reaction was concentrated and the residue wasdiluted with water and 1M hydrochloric acid. The reaction was extractedtwice with EtOAc, and the combined organic layers were washed withsaturated sodium chloride. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated to yield 42 mg of the titlecompound (80% yield). MS (apci) m/z=458.1 (M+H).

EXAMPLE 1586-Chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of 3-phenylcyclohexanone: To a solution ofphenylboronic acid (0.630 g, 5.17 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.0193 g, 0.0310 mmol) in10:1 dioxane/water (2.5 ml) was addedacetylacetonatobis(ethylene)rhodium(I) (0.00800 g, 0.0310 mmol), and thereaction was degassed with argon. To this was added cyclohex-2-enone(0.100 ml, 1.03 mmol), and the reaction was heated to 120° C. for 16hours in a screw-top vial. The reaction was allowed to cool to ambienttemperature, diluted with EtOAc, and washed with twice with saturatedsodium bicarbonate and once with saturated sodium chloride. The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was purified on a Biotage SP1 systemeluting with a linear gradient of 5-50% EtOAc in hexanes to yield 60 mgof the title compound (33.3% yield).

Step B: Preparation of 3-phenylcyclohexanone oxime: To a solution of3-phenylcyclohexanone (0.060 g, 0.3444 mmol) in 95% ethanol (2 ml) wasadded 50% hydroxylamine in water (0.2110 ml, 3.444 mmol), and thereaction was stirred at ambient temperature overnight. The reaction wasdiluted with EtOAc and washed with water and saturated sodium chloride.The organic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated to yield 60 mg of the title compound (92.07% yield).

Step C: Preparation of 3-phenylcyclohexanamine: To a solution of3-phenylcyclohexanone oxime (0.060 g, 0.32 mmol) in THF (2 ml) was added1M lithium aluminum hydride in THF (0.67 ml, 0.67 mmol), and thereaction was heated to reflux for 3 hours. The reaction was cooled toambient temperature and water (0.0254 ml), 1M sodium hydroxide (0.0254ml), and additional water (0.0762 ml) were added sequentially, and thereaction was stirred for 15 minutes. The reaction was diluted with EtOAcand filtered. The filtrate was concentrated to yield 41 mg of the titlecompound (74% yield).

Step D: Preparation of ethyl6-chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid (83.9 mg, 0.223 mmol), N,N-dimethylpyridin-4-amine (2.72 mg, 0.0223mmol), and 3-phenylcyclohexanamine (41 mg, 0.234 mmol) in DMF (1.2 ml)was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (47.0 mg, 0.245 mmol), and the reaction was stirredovernight at ambient temperature. The reaction was diluted with EtOAcand washed with 1M hydrochloric acid, saturated sodium bicarbonate, andsaturated sodium chloride. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The crude material waspurified on a Biotage SP1 system to yield 58 mg of the title compound(48.7% yield).

Step E: Preparation of6-chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate(58 mg, 0.11 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodiumhydroxide (228 μl, 0.23 mmol), and the reaction was stirred for 16 hoursat ambient temperature. The reaction was concentrated and then acidifiedwith 1M HCl and extracted twice with EtOAc. The combined organic layerswere washed with saturated sodium chloride, dried over anhydrous sodiumsulfate, filtered, and concentrated to yield 55 mg of the title compound(100% yield). MS (apci) m/z=506.1 (M+H).

EXAMPLE 1596-Chloro-7-(4-(3-(3-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substituting3-chlorophenylboronic acid for phenylboronic acid. MS (apci) m/z=537.8(M+H).

EXAMPLE 1606-Chloro-7-(4-(3-(4-methylphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substituting4-methylphenylboronic acid for phenylboronic acid. MS (apci) m/z=520.1(M+H).

EXAMPLE 1616-Chloro-7-(4-(3-(4-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substituting4-methoxyphenylboronic acid for phenylboronic acid. MS (apci) m/z=536.1(M+H).

EXAMPLE 1626-Chloro-7-(4-(3-(4-(methylthio)phenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substituting4-(methylthio)phenylboronic acid for phenylboronic acid. MS (apci)m/z=552.0 (M+H).

EXAMPLE 1636-Chloro-7-(4-(3-(3-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of 158, substituting3-methoxyphenylboronic acid for phenylboronic acid. MS (apci) m/z=536.0(M+H).

EXAMPLE 164 Sodium6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate

Steps A-E: Preparation of6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Prepared according to the method of Example 158, substituting4-chlorophenylboronic acid for phenylboronic acid.

Step F: Preparation of sodium6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.032 g, 0.0592 mmol) in methanol (2 ml) was added 0.5M sodiummethanolate in methanol (0.121 ml, 0.0604 mmol), and the reaction wasstirred overnight. The reaction was concentrated to yield 33 mg of thetitle compound (99.1% yield). MS (apci) m/z=540.0 (M−Na+2H).

EXAMPLE 1656-chloro-7-(4-(3-phenylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=492.1 (M+H).

EXAMPLE 1666-Chloro-7-(4-(3-p-tolylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substituting4-methylphenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=506.1 (M+H).

EXAMPLE 1676-Chloro-7-(4-(3-(3-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Prepared according to the method of Example 158, substituting3-chlorophenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=526.1 (M+H).

EXAMPLE 168 Sodium6-chloro-7-(4-(3-(4-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting4-chlorophenylboronic acid for phenylboronic acid substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=526.1 (M−Na+2H).

EXAMPLE 169 Sodium6-chloro-7-(4-(3-(3-methylphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting3-methylphenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=506.1 (M−Na+2H).

EXAMPLE 170 Sodium6-chloro-7-(4-(3-(3-(trifluoromethyl)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting reagent3-(trifluoromethyl)phenylboronic acid for phenylboronic acid andsubstituting cyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=560.1(M−Na+2H).

EXAMPLE 171 Sodium6-chloro-7-(4-(3-(3-fluorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting3-fluorophenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=510.1 (M−Na+2H).

EXAMPLE 172 Sodium6-chloro-7-(4-(3-(3-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting3-(methylthio)phenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=538.0 (M−Na+2H).

EXAMPLE 173 Sodium6-chloro-7-(4-(3-(3,4-dichlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting3,4-dichlorophenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=560.0 (M−Na+2H).

EXAMPLE 174 Sodium6-chloro-7-(4-(3-(4-methoxyphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting4-methoxyphenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=522.1 (M−Na+2H).

EXAMPLE 175 Sodium6-chloro-7-(4-(3-(4-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 158, substituting4-(methylthio)phenylboronic acid for phenylboronic acid and substitutingcyclopenten-2-one for cyclohexen-2-one. MS (apci) m/z=538.1 (M−Na+2H).

EXAMPLE 176 Sodium6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of tert-butyl 4-(4-chlorophenyl)cyclohexylcarbamate:To a solution of 4-(4-chlorophenyl)cyclohexanecarboxylic acid (1.01 g,4.231 mmol) and triethylamine (0.5897 ml, 4.231 mmol) in tert-butanol(22 ml) was added diphenyl phosphorazidate (0.9147 ml, 4.231 mmol), andthe reaction was heated to reflux for 16 hours. The reaction was dilutedwith EtOAc and washed with 1M hydrochloric acid, saturated sodiumbicarbonate, and saturated sodium chloride. The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated. The crudematerial was on a Biotage SP1 system eluting with a linear gradient of5-50% EtOAc in hexanes to yield 760 mg of the title compound (57%yield).

Step B: Preparation of 4-(4-chlorophenyl)cyclohexanamine: To a solutionof tert-butyl 4-(4-chlorophenyl)cyclohexylcarbamate (0.760 g, 2.45 mmol)in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml), and thereaction was stirred at ambient temperature for 2 hours. The reactionwas concentrated, taken up in water, and 1M NaOH was added until the pHwas >13. The aqueous layer was extracted twice with dichloromethane, andthe combined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated to yield 371 mg of the title compound (72.1%yield).

Step C: Preparation of ethyl 6-chloro-7-(4-(4-(4-chlorophenol)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate: To a solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g,0.13 mmol), N,N-dimethylpyridin-4-amine (0.0016 g, 0.013 mmol), and4-(4-chlorophenyl)cyclohexanamine (0.042 g, 0.20 mmol) in DMF (1 ml) wasadded N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.031 g, 0.16 mmol), and the reaction was stirredovernight at ambient temperature. The reaction was diluted with EtOAcand washed with 1M hydrochloric acid, saturated sodium bicarbonate, andsaturated sodium chloride. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated to yield 65 mg of the titlecompound (86% yield).

Step D: Preparation of6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a suspension of ethyl6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate(0.065 g, 0.11 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodiumhydroxide (0.24 ml, 0.24 mmol), and the reaction was stirred for 16hours at ambient temperature. The reaction was concentrated, taken up inwater, acidified with 1M hydrochloric acid, and extracted twice withEtOAc. The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated to yield 45 mg of the title compound(73% yield).

Step E: Preparation of sodium 6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate: To a suspension of6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.045 g, 0.0833 mmol) in 1:1 THF/methanol (5 ml) was added 0.5Msodium methanolate in methanol (0.170 ml, 0.0849 mmol), and the reactionwas stirred for 3 weeks, then concentrated to yield 47 mg of the titlecompound (100% yield). MS (apci) m/z=562.1 (M−Na+2H).

EXAMPLE 177 Sodium6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of 3-phenylcyclobutanone oxime: To a solution of3-phenylcyclobutanone (0.198 g, 1.354 mmol) in 95% ethanol (7 ml) wasadded 50% hydroxylamine in water (0.8300 ml, 13.54 mmol), and thereaction was stirred for 16 hours at ambient temperature. The reactionwas diluted with EtOAc and washed with water and saturated sodiumchloride. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated to yield 167 mg of the title compound (76.49%yield).

Step B: Preparation of 3-phenylcyclobutylamine: To a solution of3-phenylcyclobutanone oxime (0.167 g, 1.04 mmol) in THF (5 ml) was added1M lithium aluminum hydride in THF (2.18 ml, 2.18 mmol) dropwise over 3minutes. The reaction was heated to reflux for 4 hours, then cooled toambient temperature. Water (0.083 ml), 1M sodium hydroxide (0.083 ml),and additional water (0.248 ml) were added, and the reaction was stirredan additional 30 minutes. The reaction was filtered, and the solids werewashed with THF. The filtrates were combined and concentrated to yield101 mg of the title compound (66.2% yield).

Step C: Preparation of ethyl6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)) chroman-4-carboxylate: To asolution of 3-phenylcyclobutanamine (0.101 g, 0.686 mmol) in DMF (2 ml)was added 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(0.129 g, 0.343 mmol), N,N-dimethylpyridin-4-amine (0.00838 g, 0.0686mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.0789 g, 0.412 mmol), and the reaction was stirred for16 hours at ambient temperature. The reaction was diluted with EtOAc andwashed with 1M hydrochloric acid, saturated sodium bicarbonate, andsaturated sodium chloride. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The crude material was on aBiotage SP1 system eluting with a 5-70% EtOAc in hexanes linear gradientto yield 86 mg of the title compound (49.5% yield).

Step D: Preparation of6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylate(0.086 g, 0.17 mmol) in 3:1 THF/ethanol (4 ml) was added 1M sodiumhydroxide (0.36 ml, 0.36 mmol), and the reaction was stirred overnight.The reaction was concentrated, taken up in water, acidified with 1Mhydrochloric acid, and extracted twice with EtOAc. The combined organiclayers were washed with saturated sodium chloride, dried over Na₂SO₄,filtered, and concentrated to yield 67 mg of the title compound (82%yield).

Step E: Preparation of sodium6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.067 g, 0.140 mmol) in methanol (2 ml) was added 0.5M sodiummethanolate in methanol (0.294 ml, 0.147 mmol), and the reaction wasstirred for 16 hours. The reaction was concentrated to yield 70 mg ofthe title compound (99.9% yield). MS (apci) m/z=471.1 (M−Na+2H).

EXAMPLE 178 Sodium6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid (0.100 g, 0.2654 mmol) in dichloromethane (1.5 ml) and DMF (1 drop)was added oxalyl dichloride (0.02778 ml, 0.3185 mmol), and the reactionwas stirred for 30 minutes. N-ethyl-N-isopropylpropan-2-amine (0.1112ml, 0.6370 mmol) and 2-amino-3-(4-chlorophenyl)propan-1-ol (0.06405 g,0.3450 mmol) were added, and the reaction was stirred for 16 hours. Thereaction was diluted with EtOAc and washed with 1M hydrochloric acid,saturated sodium bicarbonate, and saturated sodium chloride. The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was purified on a Biotage SP1 systemeluting with 25-100% EtOAc in hexanes to yield 111 mg of the titlecompound (76.82% yield).

Step B: Preparation of6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate(0.111 g, 0.204 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodiumhydroxide (0.428 ml, 0.428 mmol), and the reaction was stirredovernight. It was concentrated and then taken up in water. It was thenacidified with 1M hydrochloric acid and extracted twice with EtOAc. Thecombined organic layers were washed with saturated sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated to yield87 mg of the title compound (82.6% yield).

Step C: Preparation of sodium6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.087 g, 0.168 mmol) in methanol (2 ml) was added 0.5M sodiummethanolate in methanol (0.354 ml, 0.177 mmol), and the reaction wasstirred for 2 hours. It was concentrated, taken up in dichloromethaneand hexanes, and concentrated again to yield 87 mg of the title compound(95.9% yield). MS (apci) m/z=515.9 (M−Na+2H).

EXAMPLE 179 Sodium6-chloro-7-(4-(3,3-dimethylbutylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 178, substituting2-cyclohexanamine hydrochloride for2-amino-3-(4-chlorophenyl)propan-1-ol. MS (apci) m/z=432.2 (M−Na+2H).

EXAMPLE 180 Sodium6-chloro-7-(4-(2-cyclohexylethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 178, substituting2-cyclohexanamine hydrochloride for2-amino-3-(4-chlorophenyl)propan-1-ol and increasing the amount ofN-ethyl-N-isopropylpropan-2-amine used in Step A from 2.2 equivalents to3.5 equivalents. MS (apci) m/z=458.2 (M−Na+2H).

EXAMPLE 181 Sodium6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate

Step A: Preparation of 4-bromo-N-(4-chlorophenethyl)-3-methylbenzamide:To a suspension of 4-bromo-3-methylbenzoic acid (0.500 g, 2.325 mmol) indichloromethane (10 ml) and DMF (1 drop) was added oxalyl dichloride(0.2231 ml, 2.558 mmol), and the reaction was stirred for 30 minutes.N-ethyl-N-isopropylpropan-2-amine (0.8934 ml, 5.115 mmol) and2-(4-chlorophenyl)ethanamine (0.3557 ml, 2.558 mmol) were added, and thereaction was stirred for 1 hour at ambient temperature. The reaction wasdiluted with EtOAc and washed with 1M hydrochloric acid, saturatedsodium bicarbonate, and saturated sodium chloride. The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude material was purified by recrystallization from EtOAc and hexanesto yield 400 mg of the title compound (48.78% yield).

Step B: Preparation of ethyl6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate:To a solution of 4-bromo-N-(4-chlorophenethyl)-3-methylbenzamide (0.0831g, 0.236 mmol), ethyl 6-chloro-7-hydroxychroman-4-carboxylate (0.050 g,0.195 mmol), and 2-(dimethylamino)acetic acid (0.0104 g, 0.101 mmol) indioxane (1 ml) degassed with argon was added cesium carbonate (0.133 g,0.409 mmol) and copper(I) chloride (0.0100 g, 0.101 mmol). The reactionwas sealed in a screw-cap vial and heated to 100° C. for 16 hours. Thereaction was cooled to ambient temperature, then loaded directly onto aBiotage SP1 system, eluting with a linear gradient of 5-70% EtOAc inhexanes to yield 22 mg of the title compound (21% yield).

Step C: Preparation of6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate(0.022 g, 0.042 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodiumhydroxide (0.087 ml, 0.087 mmol). The reaction was stirred overnight andthen concentrated. The residue was taken up in water and acidified with1M hydrochloric acid and extracted twice with EtOAc. The combinedorganic layers were washed with saturated sodium chloride, dried overanhydrous sodium sulfate, filtered, and concentrated. The crude materialwas purified by preparatory thin layer chromatography eluting with95:5:1 dichloromethane/methanol/glacial acetic acid to yield 11 mg ofthe title compound (53% yield).

Step D: Preparation of sodium6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylicacid (0.011 g, 0.0220 mmol) in methanol (2 ml) was added 0.5 M sodiummethanolate in methanol (0.0462 ml, 0.0231 mmol), and the reaction wasstirred at ambient temperature for 3 hours. The reaction wasconcentrated, and the residue was diluted with dichloromethane andhexanes, and concentrated again to yield 11 mg of the title compound(95.8% yield). MS (apci) m/z=500.0 (M−Na+2H).

EXAMPLE 182 Sodium6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate

Prepared according to the method of Example 181, substituting2-(2,4-dichlorophenyl)ethanamine for 2-(4-chlorophenyl)ethanamine. MS(apci) m/z=534.0 (M−Na+2H).

EXAMPLE 183 Sodium6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-3-methylphenoxy)chroman-4-carboxylate

Prepared according to the method of Example 181, substituting4-bromo-2-methylbenzoic acid for 4-bromo-3-methylbenzoic acid. MS (apci)m/z=534.0 (M−Na+2H).

EXAMPLE 184 Sodium6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of ethyl6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoicacid (0.050 g, 0.13 mmol), 2-amino-1-(4-chlorophenyl)ethanolhydrochloride (0.033 g, 0.16 mmol), N-ethyl-N-isopropylpropan-2-amine(0.030 ml, 0.17 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.018g, 0.13 mmol) in DMF (1 ml) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.031 g, 0.16 mmol), and the reaction was stirred atambient temperature for 16 hours. It was diluted with EtOAc and washedwith 10% citric acid, saturated sodium bicarbonate, and saturated sodiumchloride. It was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was on a Biotage SP1 system using a25-100% EtOAc/hexanes linear gradient to yield 56 mg of the titlecompound (80% yield).

Step B: Preparation of6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylate(0.056 g, 0.11 mmol) in a solution of 3:1 THF/ethanol (2 ml) was added1M sodium hydroxide (0.22 ml, 0.22 mmol), and the reaction was stirredfor 16 hours. The reaction was concentrated, taken up in water,acidified with 1M hydrochloric acid, and extracted twice with EtOAc. Thecombined organic layers were washed with saturated sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated to yield46 mg of the title compound (87% yield).

Step C: Preparation of sodium6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.046 g, 0.092 mmol) in methanol (1 ml) was added 0.5M sodiummethanolate in methanol (0.18 ml, 0.092 mmol), and the reaction wasstirred at ambient temperature for 16 hours. It was concentrated, takenup in dichloromethane and hexanes, and concentrated again to yield 46 mgof the title compound (96% yield). MS (apci) m/z=501.8 (M−Na+2H).

EXAMPLE 185 Sodium6-chloro-7-(4-(2-(2-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 184, substituting2-amino-1-(4-chlorophenyl)ethanol hydrochloride for2-amino-1-(2-chlorophenyl)ethanol hydrochloride. MS (apci) m/z=501.8(M−Na+2H).

EXAMPLE 186 Sodium6-chloro-7-(4-(2-cyclopentylethylcarbamoyl)phenoxy)chroman-4-carboxylate

Prepared according to the method of Example 184, substituting2-amino-1-(4-chlorophenyl)ethanol hydrochloride with2-cyclopentylethanamine and omitting N-ethyl-N-isopropylpropan-2-amine.MS (apci) m/z=444.2 (M−Na+2H).

EXAMPLE 187 Sodium7-(4-(1-oxaspiro[4,4]nonan-3-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate

Prepared according to the method of Example 184, substituting2-amino-1-(4-chlorophenyl)ethanol hydrochloride with1-oxaspiro[4.4]nonan-3-amine and omittingN-ethyl-N-isopropylpropan-2-amine. MS (apci) m/z=472.0 (M−Na+2H).

EXAMPLE 188 Sodium6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of [N-[(p-nitrophenyl)sulfonyl]imino]phenyliodinane:To a solution of 4-nitrobenzenesulfonamide (0.628 g, 3.10 mmol) andpotassium hydroxide (0.410 g, 6.21 mmol) in MeOH (10 ml) at 0° C. wasadded iodobenzene diacetate (1.00 g, 3.10 mmol), and the reaction wasallowed to warm to ambient temperature and stir for 4 hours. Thereaction was filtered, and the solids were washed with water and driedunder reduced pressure to yield 980 mg of the title compound (78.1%yield).

Step B: Preparation of2-(4-chlorophenol)-1-(4-nitrophenylsulfonyl)aziridine: To a suspensionof 1-chloro-4-vinylbenzene (0.1195 ml, 0.9957 mmol),tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.01856 g, 0.04979mmol), and 4 angstrom molecular sieves (300 mg) in dry acetonitrile (2.5ml) degassed with argon was added[N-[(p-nitrophenyl)sulfonyl]imino]phenyliodinane (0.6037 g, 1.494 mmol)portion-wise over 2 hours as a solid. It was stirred overnight underargon, then was loaded directly onto a Biotage SP1 system eluting with a2-30% linear gradient of EtOAc in hexanes to yield 276 mg of the titlecompound (81.8% yield).

Step C: Preparation ofN-(2-(4-chlorophenyl)-2-methoxyethyl)-4-nitrobenzenesulfonamide:2-(4-Chlorophenyl)-1-(4-nitrophenylsulfonyl)aziridine (0.276 g, 0.815mmol) was dissolved in 8 ml of methanol and 4 ml of dichloromethane. Thereaction was stirred at ambient temperature for 5 days, and thenconcentrated. The crude material was on a Biotage SP1 system elutingwith a 5-50% linear gradient of EtOAc in hexanes to yield 231 mg of thetitle compound (76.5% yield).

Step D: Preparation of tert-butyl2-(4-chlorophenyl)-2-methoxyethylcarbamate: A solution ofN-(2-(4-chlorophenyl)-2-methoxyethyl)-4-nitrobenzenesulfonamide (0.231g, 0.6230 mmol), benzenethiol (0.1910 ml, 1.869 mmol), and potassiumcarbonate (0.3444 g, 2.492 mmol) in 49:1 acetonitrile/DMSO (15 ml) washeated to 50° C. for 3 hours. The reaction was cooled to ambienttemperature and di-tert-butyl dicarbonate (0.6798 g, 3.115 mmol) wasadded. The reaction was stirred for 1 hour. The reaction wasconcentrated and the crude material was loaded directly onto a BiotageSP1 system, eluting with a 5-40% linear gradient of EtOAc in hexanes toyield 129 mg of the title compound (72.46% yield).

Step E: Preparation of 2-(4-chlorophenol)-2-methoxyethanamine: To asolution of tert-butyl 2-(4-chlorophenyl)-2-methoxyethylcarbamate (0.129g, 0.451 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid(5 ml), and the reaction was stirred at ambient temperature for 16hours. The reaction was concentrated and taken up in water. Sodiumhydroxide (1M) was added until the pH was >13. The mixture was extractedtwice with dichloromethane, and the combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to yield 71 mgof the title compound (84.7% yield).

Step F: Preparation of ethyl6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 2-(4-chlorophenyl)-2-methoxyethanamine (0.071 g, 0.38mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.060g, 0.16 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.022 g, 0.16mmol) in DMF (1 ml) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.037 g, 0.19 mmol), and the reaction was stirred atambient temperature overnight. The reaction was diluted with EtOAc andwashed with 1M hydrochloric acid, saturated sodium bicarbonate, andsaturated sodium chloride. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated. The crude material wasloaded onto a Biotage SP1 system, eluting with a linear gradient of5-70% EtOAc in hexanes to yield 67 mg of the title compound (77% yield).

Step G: Preparation of6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylate(0.067 g, 0.12 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodiumhydroxide (0.26 ml, 0.26 mmol). The reaction was stirred for 16 hours,and then concentrated, diluted with water, and acidified with 1Mhydrochloric acid. The mixture was extracted twice with EtOAc, and thecombined organic layers were washed with saturated sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated to yield56 mg of the title compound (88% yield).

Step F: Preparation of sodium6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.056 g, 0.108 mmol) in methanol (2 ml) was added 0.5M sodiummethanolate in methanol (0.228 ml, 0.114 mmol), and the reaction wasstirred for 16 hours. The reaction was concentrated, and the residue wastaken up in dichloromethane and hexanes, and concentrated to yield 56 mgof the title compound (95.9% yield). MS (apci) m/z=515.8 (M−Na+2H).

EXAMPLE 189 Sodium6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylate

Step A: Preparation of2-(2,4-dichlorophenyl)-2-(trimethylsilyloxy)acetonitrile: To a solutionof 2,4-dichlorobenzaldehyde (1.00 g, 5.71 mmol) in neattrimethylsilanecarbonitrile (7.62 ml, 57.1 mmol) was added zinc(II)iodide (0.0912 g, 0.286 mmol). The reaction was stirred for 3 hours,then diluted with EtOAc and washed twice with saturated sodiumbicarbonate and once with saturated sodium chloride. The organic layerwas dried over anhydrous sodium sulfate, filtered, and concentrated toyield 1.57 g of the title compound (100% yield).

Step B: Preparation of 2-(2,4-dichlorophenyl)-2-fluoroacetonitrile: To asolution of 2-(2,4-dichlorophenyl)-2-(trimethylsilyloxy)acetonitrile(1.57 g, 5.73 mmol) in dichloromethane (20 ml) under argon at −78° C.was added (diethylamino)sulfur trifluoride (1.51 ml, 11.5 mmol) dropwiseover 15 minutes. The reaction was stirred at this temperature for 20minutes, then warmed to 0° C. and allowed to stir for an additional 30minutes. The reaction was poured onto a mixture of ice water andsaturated sodium bicarbonate and allowed to stir for 30 minutes. Themixture was extracted with ether twice, and the combined organic layerswere washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated to yield 1.05 g of thetitle compound (89% yield).

Step C: Preparation of 2-(2,4-dichlorophenyl)-2-fluoroethanamine: To asolution of 2-(2,4-dichlorophenyl)-2-fluoroacetonitrile (0.263 g, 1.29mmol) in THF (2 ml) was added borane-DMS complex (0.134 ml, 1.42 mmol),and the reaction was heated to reflux under argon for one hour. Thereaction was cooled to ambient temperature, and 0.4 ml of concentratedhydrochloric acid were added. The reaction mixture was again heated toreflux for 30 minutes, then cooled to ambient temperature and treatedwith 1M sodium hydroxide until the pH reached 13. The reaction wasextracted three times with ether, and the combined organic layers werewashed with saturated sodium chloride, dried over anhydrous potassiumcarbonate, filtered, and concentrated to yield 217 mg of the titlecompound (80.9% yield).

Step C: Preparation of ethyl6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of 2-(2,4-dichlorophenyl)-2-fluoroethanamine (0.126 g,0.606 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(0.114 g, 0.303 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.0412g, 0.303 mmol) in DMF (2 ml) was addedN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.0697 g, 0.363 mmol. The reaction was stirred for 16hours at ambient temperature. It was diluted with EtOAc and washed with1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodiumchloride. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated. The crude material was on a Biotage SP1system eluting with a linear gradient of 5-50% EtOAc in hexanes to yield161 mg of the title compound (93.8% yield).

Step D: Preparation of6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylate(0.161 g, 0.284 mmol) in 3:1 THF/ethanol (4 ml) was added sodiumhydroxide (0.341 ml, 0.341 mmol), and the reaction was stirred for 3days at ambient temperature. The reaction was concentrated, taken up inwater, acidified with 1M hydrochloric acid, and extracted twice withEtOAc. The combined organic layers were washed with saturated sodiumchloride, dried over anhydrous sodium sulfate, filtered, andconcentrated to yield 121 mg of the title compound (79.7% yield).

Step E: Preparation of sodium6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a solution of6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (0.122 g, 0.226 mmol) in methanol (2 ml) was added 0.5 M sodiummethanolate in methanol (0.476 ml, 0.238 mmol), and the reaction wasstirred overnight. The reaction was concentrated, taken up indichloromethane and hexanes, and concentrated again to yield 122 mg ofthe title compound as a white solid (96.1% yield). MS (apci) m/z=537.7(M−Na+2H).

Table 1 provides additional compounds that were made by methodsdescribed herein.

MS or Ex. # Structure Name ¹H NMR Data 190

sodium 6-chloro-7-(4- (3,5-dimethoxyphenethyl- carbamoyl)phenoxy)chroman-4-carboxylate LCMS (APCI) = 512.2 (M − Na + 2H) 191

sodium 6-chloro-7-(4-(3- chloro-2-methoxyphen- ethylcarbamoyl)phenoxy)chroman-4-carboxylate LCMS (APCI) = 516.1 (M − Na + 2H) 192

sodium 6-chloro-7-(4-(4- chloro-2-(trifluoro- methyl)phenethyl-carbamoyl)phenoxy) chroman-4-carboxylate LCMS (APCI) = 554.1 (M − Na +2H) 193

sodium 7-(4-(2- (benzo[d][1,3]dioxol-4- yl)ethylcarbamoyl) phenoxy)-6-chlorochroman-4- carboxylate MS (apci) m/z = 495.9 (M − Na + 2H) 194

sodium 6-chloro-7-(4-(2- (1-(4-(trifluoromethyl) phenyl)-1H-pyrrol-2-yl)ethylcarbamoyl)phenoxy) chroman-4- carboxylate MS (apci) m/z = 584.9(M − Na + 2H) 195

sodium 6-chloro-7-(4-(2- (4-chlorophenyl)-2,2- difluoroethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 522 (M − Na + 2H). 196

sodium 6-chloro-7-(4-(2- ethylphenethylcarbamoyl) phenoxy)chroman-4-carboxylate MS (apci) m/z = 480.0 (M − Na + 2H). 197

sodium 6-chloro-7-(4-(2- (2,4-dichlorophenyl)-2- hydroxyethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 537.7 (M − Na + 2H). 198

sodium 6-chloro-7-(4-(4- chloro-2-ethoxyphen- ethylcarbamoyl)phenoxy)chroman-4-carboxylate MS (apci) m/z = 530 (M − Na + 2H). 199

sodium 6-chloro-7-(4-(4- chloro-2-(cyclopropyl- methoxy)phenethylcarba-moyl)phenoxy)chroman- 4-carboxylate MS (apci) m/z = 556 (M − Na + 2H).200

sodium 6-chloro-7-(4-(4- chloro-2-(2- methoxyethoxy)phenethyl-carbamoyl)phenoxy) chroman-4-carboxylate MS (apci) m/z = 560 (M − Na +2H). 201

sodium 6-chloro-7-(4- (4,5-dichloro-2- ethoxyphenethylcarba-moyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 564 (M − Na + 2H).202

sodium 6-chloro-7-(4-(4- chloro-2-isopropoxy- phenethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 544 (M − Na + 2H). 203

sodium 6-chloro-7-(4-(4- chloro-2-(trifluoro- methoxy)phenethyl-carbamoyl)phenoxy) chroman-4-carboxylate MS (apci) m/z = 570 (M − Na +2H). 204

sodium 6-chloro-7-(4- (3,5-dichlorophenethyl- carbamoyl)phenoxy)chroman-4-carboxylate MS (apci) m/z = 522 (M − Na + 2H). 205

sodium 6-chloro-7-(4- ((1,2,3,4-tetrahydro- naphthalen-1-yl)methyl-carbamoyl)phenoxy) chroman-4-carboxylate MS (apci) m/z = 492 (M − Na +2H). 206

sodium 6-chloro-7-(4-(2- (4-chlorophenoxy) phenethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 578.1 (M + 2H − Na) 207

sodium 6-chloro-7-(4-(4- chloro-2-phenoxyphen- ethylcarbamoyl)phenoxy)chroman-4-carboxylate MS (apci) m/z = 578.1 (M + 2H − Na) 208

sodium 6-chloro-7-(4-(4- chloro-2-(4- chlorophenoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylate MS (apci) m/z = 612.1 (M + 2H −Na) 209

sodium 6-chloro-7-(4-(2- (3-chlorophenoxy) phenethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 578.1 (M + 2H − Na) 210

sodium 6-chloro-7-(4-(2- (2-chlorophenoxy) phenethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 578.1 (M + 2H − Na) 211

sodium 6-chloro-7-(4-(4- chloro-2-(3- chlorophenoxy)phenethylcarbamoyl)phenoxy) chroman- 4-carboxylate MS (apci) m/z = 612.0 (M + 2H− Na) 212

sodium 6-chloro-7-(4-(2- (3,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl) phenoxy)chroman-4- carboxylate MS (apci) m/z =630.0 (M + 2H − Na) 213

sodium 6-chloro-7-(4-(2- (2,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl) phenoxy)chroman-4- carboxylate MS (apci) m/z =630.0 (M + 2H − Na) 214

sodium 6-chloro-7-(4-(4- chloro-2-(2-fluoro- ethoxy)phenethylcarbamoyl)phenoxy)chroman-4- carboxylate MS (apci) m/z = 547.9 (M + 2H − Na) 215

sodium 6-chloro-7-(4-(4- chloro-2-(3- fluoropropoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylate MS (apci) m/z = 562 (M + 2H −Na) 216

sodium 6-chloro-7-(4-(2- chloro-6-methoxyphen- ethylcarbamoyl)phenoxy)chroman-4-carboxylate MS (apci): 515.9 (M + 2H − Na) 217

sodium 6-chloro-7-(4- (2,6-dimethoxyphen- ethylcarbamoyl)phenoxy)chroman-4-carboxylate MS (apci): 512.0 (M + 2H − Na) 218

5-chloro-7-(4-(4- chlorophenethylcarbamoyl) phenoxy)chroman-4-carboxylic acid MS (apci, pos) m/z = 486 219

7-(4-((1-(4-chlorophenyl) cyclopropyl)methylcarba-moyl)phenoxy)-6-cyano- chroman-4-carboxylic acid MS (apci, pos) m/z =503 220

6-chloro-7-(4-(2- phenoxyethylcarbamoyl) phenoxy)chroman-4- carboxylicacid MS (apci, pos) m/z = 468 221

7-(4-(2,4-bis(trifluoro- methyl)phenethylcarba- moyl)phenoxy)-6-chloro-chroman-4-carboxylic acid ¹H NMR (400 MHz, D₆ DMSO) δ 8.02 (d, 1H, J =8.1 Hz), 7.97 (s, 1H), 7.83-7.81 (c, 2H), 7.76 (d, 1H, J = 8.0 Hz), 7.55(s, 1H), 6.91 (d, 2H, J = 8.6 Hz), 6.51 (s, 1H), 4.21 (m, 1H), 4.11 (m,1H), 3.60 (m, 1H), 3.55-3.52 (c, 2H), 3.23 (m, 1H), 3.09 (m, 1H), 2.20(m, 1H), 1.76 (m, 1H). 222

6-chloro-7-(4-(2,4,6- trimethoxyphenethyl- carbamoyl)phenoxy)chroman-4-carboxylic acid MS (apci, pos) m/z = 542 223

6-chloro-7-(4-(4- (difluoromethoxy)phenethyl- carbamoyl)phenoxy)chroman-4-carboxylic acid MS (apci, pos) m/z = 518 224

6-chloro-7-(4-(2,6-dichloro- 4-methoxyphenethyl- carbamoyl)phenoxy)chroman-4-carboxylic acid MS (apci, pos) m/z = 552 225

6-chloro-7-(4-(2,4-diethoxy- phenethylcarbamoyl)phen-oxy)chroman-4-carboxylic acid MS (apci, pos) m/z = 540 226

6-chloro-7-(4-(2-chloro- 4,6-dimethoxyphenethyl- carbamoyl)phenoxy)chroman-4-carboxylic acid MS (esi, pos) m/z = 546 227

6-chloro-7-(4-(4-ethoxy-2- methoxyphenethylcarba-moyl)phenoxy)chroman-4- carboxylic acid MS (esi + apci, pos) m/z = 526228

6-chloro-7-(4-(2-ethoxy- 4-methoxyphenethyl- carbamoyl)phenoxy)chroman-4-carboxylic acid MS (esi + apci, pos) m/z = 526 229

6-chloro-7-(4-(4-chloro-2- (methylthio)phenethyl- carbamoyl)phenoxy)chroman-4-carboxylic acid MS (apci, pos) m/z = 532 230

6-chloro-7-(4-(4-chloro-2- fluorophenethylcarba- moyl)phenoxy)chroman-4-carboxylic acid MS (esi + apci, pos) m/z = 504 231

6-chloro-7-(4-((5-chloro-2,3- dihydro-1H-inden-1- yl)methylcarbamoyl)phenoxy)chroman-4- carboxylic acid MS (apci, pos) m/z = 512 232

6-chloro-7-(4-(2-cyclo- propyl-4-(trifluoromethyl) phenethylcarbamoyl)phenoxy)chroman- 4-carboxylic acid MS (esi + apci, pos) m/z = 560

EXAMPLE 2336-Chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid

Step A: Preparation of ethyl6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a suspension of 2-(4-chloro-2-methoxyphenyl)ethanamine hydrochloride(Preparation 8; 23.4 g, 105 mmol) in DCM (200 ml) was addedtriethylamine (16.8 ml, 120 mmol), and the mixture was allowed to stirfor 30 minutes (solids did not go into solution). To this was addedsequentially 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1; 37.8 g, 100 mmol, 1H-benzo[d][1,2,3]triazol-1-ol hydrate(15.4 g, 100 mmol), andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (23.1 g, 120 mmol), and the reaction was allowed to stirovernight (all solids went into solution after 2 hours). The reactionwas diluted with EtOAc (600 ml) and washed with 600 mL portions of 1MHCl, saturated aqueous bicarbonate, and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated. The residue wastaken up in hot ethyl acetate (500 ml) and was crystallized by theaddition of hexanes (1.5 L) to yield ethyl6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(51.1 g, 93.9 mmol).

Step B: Preparation of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(31.0 g, 56.9 mmol) in 3:1 THF/EtOH (200 ml) was added sodium hydroxide(120 ml, 120 mmol), and the reaction was allowed to stir overnight atambient temperature, at which point it was complete as determined bythin layer chromatography. The reaction was concentrated to about 25%volume, taken up in 100 ml of EtOH and 100 ml of water, and acidifiedwith 10 ml of concentrated HCl with stirring. The product initiallyoiled out, but became a solid. The solids were collected by filtrationand washed with 200 ml of water to yield6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (24.7 g, 47.8 mmol) as a white solid.

Step C: Preparation of6-Chloro-7-(4-(4-chloro-2-hydroxyphenethyl-carbamoyl)phenoxy)chroman-4-carboxylicacid: To a stirred, chilled (0° C.) solution of boron trichloride indichloromethane (13.6 mL; 1.0 M; 7 eq.) was added, portionwise over 2minutes, solid6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (1.0 g; 1.94 mmol) under nitrogen atmosphere. The resulting mixturewas allowed to warm to ambient temperature, stirred for 8 hours and thenheated to 35° C. for 24 hours. The reaction was quenched with 5 mL water(significant effervescence observed while adding first 2 mL) and then 6mL of saturated Na₂CO₃ was added to bring the pH to 4. During the last 1mL of addition, significant amounts of precipitates formed in the lowerorganic layer. The warm bath was removed and replaced with an ice bath.The material was stirred for 5 minutes in ice bath, then solidscollected on a medium frit, washing once with 5 mL chilled MTBE. Thismaterial was purified via Biotage chromatography with methanol in ethylacetate to provide the desired6-chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (195 mg). MS (apci, neg) m/z=500. ¹H NMR (400 MHz, D6 DMSO) δ 8.45(t, 1H), 7.82, (d, 2H), 7.46 (s, 1H), 7.06 (d, 1H), 6.95 (d, 2H), 6.83(d, 1H), 6.75 (dd, 1H), 6.60 (s, 1H), 4.22 (m, 1H), 4.12 (t, 1H), 3.72(br s, 1H), 3.60 (t, 1H), 2.76 (t, 2H), 2.22 (m, 1H), 1.99 (m, 1H), 1.76(m, 1H).

EXAMPLE 234 Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Preparation of Ethyl7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:To a stirred solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation1; 1.32 g; 3.52 mmol), 1-hydroxybenzotriazole hydrate (0.59 g; 3.85mmol) and 2-(2-bromo-4-chlorophenyl)ethanamine (Preparation 5; 0.904 g;3.85 mmol) in dry dimethylformamide (10 mL) was added1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.806 g;4.02 mmol) at ambient temperature. After stirring at ambient temperaturefor 5 hours, the solution was diluted with 100 mL of water, stirred for10 minutes longer and then extracted with ethyl acetate (3×15 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (Biotage 40M), eluting with hexane and ethyl acetate toprovide ethyl7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylateas a white solid (1.21 g). MS (apci, pos) m/z=594.

Step B: Preparation of Ethyl6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a stirred suspension of ethyl7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(129 mg; 0.22 mmol) in 2 mL toluene was added successively water (0.1mL), potassium phosphate (138 mg; 0.65 mmol), tricyclohexylphosphine (24mg; 0.087 mmol), and cyclopropylboronic acid (0.435 mmol) at ambienttemperature with stirring. A balloon of nitrogen with a three-way purgevalve was attached, and the flask was evacuated and refilled five timeswith nitrogen. Palladium (II) acetate (10 mg; 0.043 mmol) was added, andagain the flask was evacuated and refilled five times with nitrogen. Themixture was stirred in an oil bath set to 100° C. under the nitrogenballoon. After 4 hours the mixture was cooled to ambient temperature.The mixture was diluted with 10 mL EtOAc and 5 mL water. The mixture wastransferred to a separatory funnel and after shaking, the organic layerwas separated, dried over sodium sulfate and evaporated to give a brownoil. This material was purified by silica gel chromatography on aBiotage 25S column, eluting with 75/25 hexane/EtOAc to provide 83 mg ofethyl6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylateas a colorless oil. MS (apci, pos) m/z=554.

Step C: Preparation of 6-Chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a stirred solution ofethyl6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(83 mg; 0.15 mmol) in a mixture of 1.4 mL tetrahydrofuran and 0.7 mLethanol at ambient temperature was added 0.60 mL of 1M aqueous sodiumhydroxide. The resulting slightly cloudy mixture was vigorously stirredat ambient temperature for 1 hour, after which the reaction wasdetermined to be complete by thin layer chromatography (90/10/1chloroform/methanol/HOAc). The reaction mixture was diluted with 5 mLEtOAc and 2.5 mL of 1M HCl, then transferred to a separatory funnel.After shaking, the organic layer was washed with 2 mL brine, then driedover sodium sulfate and evaporated to give 61 mg of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid as a colorless oil. MS (apci, pos) m/z=526

Step D: Isolation of Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The racemic mixture of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid was dissolved in methanol and resolved via supercritical fluidchromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting withmethanol/carbon dioxide at 100 bar, using 1 mL injections and a flowrate of 70 mL/min. Collection of fractions containing peak 2 and removalof volatiles provided Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=526. Chiral purity (ee)>98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material.

Step E: Preparation of the sodium salt of Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The material obtained in Step D (peak 2; 83 mg) was dissolved in 1mL methanol, and 0.026 mL of 25% sodium methoxide in methanol was added.The solvent was evaporated, and the residue evaporated from ether togive 60 mg of Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid, sodium salt as an off-white solid. MS (apci, pos): m/z=526. ¹H NMR(400 MHz, D6 DMSO) δ 8.58 (t, 1H), 7.82 (d, 2H), 7.55 (s, 1H), 7.17 (d,1H), 7.14 (dd, 1H), 6.91 (m, 3H), 6.52 (s, 1H), 4.21 (dt, 1H), 4.11 (m,1H), 3.47 (q, 2H), 3.22 (t, 1H), 2.99 (t, 2H), 2.20 (m, 1H), 2.10 (m,1H), 1.78 (m, 1H), 1.09 (t, 1H), 0.96 (m, 2H), 0.69 (m, 2H). Opticalrotation: [a]²⁵ _(D)=−16.63° (c=1.00, MeOH).

During the chiral separation described in Step D, fractions containingpeak 1 were collected to provide Enantiomer 1 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=526. Chiral purity (ee)>98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material. The sodiumsalt of Enantiomer 1 was then prepared in a manner similar to thatprovided in Step E. MS (apci, pos) m/z=526. The sodium salt ofEnantiomer 1 was found to be less active than the sodium salt ofEnantiomer 2 when tested in an assay described in Example A.

EXAMPLE 235 Enantiomer 2 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Preparation of ethyl7-(4-(2-methoxy-4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:To a stirred solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation1; 1.90 g; 5.04 mmol), 1-hydroxybenzotriazole hydrate (0.85 g; 5.55mmol) and 2-(2-methoxy-4-bromophenyl)ethanamine (Preparation 6; 1.28 g;5.55 mmol) in dry dimethylformamide (15 mL) was added1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.16 g; 6.05mmol) at ambient temperature. After stirring at ambient temperature for4 hours, the solution was diluted with 150 mL of water, stirred for 10minutes longer and then extracted with ethyl acetate (3×15 mL). AqueousHCl (1M, 50 mL) was added to enable layer separation. The combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography (Biotage40M), eluting with hexane and ethyl acetate to provide ethyl7-(4-(2-methoxy-4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylateas a light yellow solid (1.81 g). MS (apci, pos) m/z=590.

Step B: Preparation of ethyl7-(4-(2-methoxy-4-cyclopropylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate:To a stirred suspension of7-(4-(2-methoxy-4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(130 mg; 0.22 mmol) in 2 mL toluene was added successively 0.1 mL water,potassium phosphate (141 mg; 0.66 mmol), tricyclohexylphosphine (25 mg;0.08 mmol), and cyclopropylboronic acid (38 mg; 0.44 mmol) at ambienttemperature with stirring. A balloon of nitrogen with a three-way purgevalve was attached, and the flask was evacuated and refilled five timeswith nitrogen. Palladium(II) acetate (10 mg; 0.04 mmol) was added, andagain the flask was evacuated and refilled five times with nitrogen. Themixture was then stirred in an oil bath set to 100° C. under thenitrogen balloon. After 3.5 hours the mixture was cooled to ambienttemperature, and the reaction was determined to be complete by thinlayer chromatography (50/50 hexane/EtOAc). The mixture was diluted with10 mL EtOAc and 5 mL water. The mixture was transferred to a separatoryfunnel and after shaking, the organic layer was dried over sodiumsulfate and evaporated to give a brown oil. The crude material waspurified by silica gel chromatography on a Biotage 25S column, elutingwith 75/25 hexane/EtOAc to give 73 mg of ethyl7-(4-(2-methoxy-4-cyclopropylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylateas a colorless oil. MS (apci, pos) m/z=550.

Step C: Preparation of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a stirred solution of ethyl7-(4-(2-methoxy-4-cyclopropylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate(0.07 g; 0.133 mmol) in a mixture of 1.2 mL THF and 0.6 mL ethanol atambient temperature was added 0.53 mL of 1M aqueous NaOH. The resultingslightly cloudy mixture was vigorously stirred at ambient temperature.After 1 hour the reaction mixture was diluted with 6 mL EtOAc and 3 mLof 1M aqueous HCl, then transferred to a separatory funnel. Aftershaking, the organic layer was washed with 2 mL brine, then dried oversodium sulfate and evaporated to give 62 mg of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid as a colorless oil. MS (apci, pos) m/z=523.

Step D: Isolation of Enantiomer 2 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The racemic mixture of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid was dissolved in methanol and resolved via supercritical fluidchromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting withmethanol/carbon dioxide at 100 bar, using 1 mL injections and a flowrate of 60 mL/min. Collection of fractions containing peak 2 and removalof volatiles provided Enantiomer 2 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=522. Chiral purity (ee)>98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material.

Step E: Preparation of the sodium salt of Enantiomer 2 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The material obtained above (peak 2;6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; 10.7 g, 20.5 mmol) was taken up in 40 ml THF and 75 ml EtOH. Thesolution was treated with sodium methoxide (41.0 ml of 0.5 M inmethanol, 20.5 mmol). The mixture remained a solution and was stirredfor 5 minutes. The sides of flask were rinsed with 50 ml ethanol and themixture was concentrated in vacuo. EtOH (100 mL) was added and themixture was concentrated in vacuo. The residue was put under high vacuumat 55° C. (sand bath temperature) for 60 hours to provide sodium(S)-6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(11.3 g, 20.8 mmol) as a white solid. MS (apci, pos) m/z=522. ¹H NMR(400 MHz, D6 DMSO) δ 7.82 (d, 2H), 7.56 (s, 1H), 6.99 (d, 1H), 6.91 (dd,2H), 6.66 (s, 1H), 6.56 (d, 1H), 6.52 (m, 1H), 4.23 (m, 1H), 4.12 (m,1H), 3.77 (s, 3H), 3.38 (m, 2H), 3.27 (m, 1H), 2.74 (t, 2H), 2.21 (m,1H), 1.84 (m, 2H), 0.90 (m, 2H), 0.65 (m, 2H).

During the chiral separation described in Step D, fractions containingpeak 1 were collected to provide Enantiomer 1 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=522. Chiral purity (ee) >98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material. The sodiumsalt of Enantiomer 1 was then prepared in a manner similar to thatprovided in Step E. MS (apci, pos) m/z=522. The sodium salt ofEnantiomer 1 was found to be less active than the sodium salt ofEnantiomer 2 when tested in an assay described in Example A.

EXAMPLE 236

Enantiomer 2 of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Preparation of Ethyl6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a stirred solution of4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation1; 0.75 g; 2.0 mmol), 1-hydroxybenzotriazole hydrate, and2-(2,4-dichloro-6-methoxyphenyl)ethanamine (Preparation 7; 0.48 g, 2.19mmol) in 6 mL DMF at ambient temperature was added solid1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g; 2.4mmol). The resulting solution was stirred at ambient temperatureovernight for convenience. The solution was diluted with 60 mL water andafter stirring for 10 minutes, the mixture was transferred to aseparatory funnel and extracted with 30 mL EtOAc. 1M HCl (30 mL) wasadded to enable layer separation. The organic layer was dried oversodium sulfate and evaporated. The residue was purified by silica gelchromatography on a Biotage 40M column, eluting with 70/30 hexane/EtOAc,to give 0.56 g of ethyl6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylateas a white glass. MS (apci, pos) m/z=578.

Step B: Preparation of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a stirred solution of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(0.56 g; 0.97 mmol) in a mixture of 10 mL tetrahydrofuran and 5 mLethanol at ambient temperature was added 3.9 mL of 1M aqueous sodiumhydroxide. The resulting slightly cloudy mixture was vigorously stirredat ambient temperature the reaction mixture was poured into a separatoryfunnel containing 100 mL ethyl acetate and 50 mL 1M aqueous hydrochloricacid. After shaking, the organic layer was washed with 20 mL brine, thendried over sodium sulfate and evaporated to give 0.60 of light yellowoil. To convert to the sodium salt, the material was dissolved in 10 mLmethanol, and 0.22 mL of 25% sodium methoxide in methanol was added. Thesolvent was evaporated, and the residue evaporated from ether to give0.54 g of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid as an off-white glass. MS (apci, pos) m/z=550. MS (apci, neg)m/z=548.

Step C: Isolation of Enantiomer 2 of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The racemic mixture of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid was dissolved in methanol and resolved via supercritical fluidchromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting withmethanol/carbon dioxide at 100 bar, using 1 mL injections and a flowrate of 70 mL/min. Collection of fractions containing peak 2 and removalof volatiles provided Enantiomer 2 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=550. Chiral purity (ee) >98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material.

Step D: Preparation of the sodium salt of Enantiomer 2 of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The material obtained in Step C (peak 2; 0.56 g; 0.97 mmol))dissolved in 10 mL methanol, and 0.22 mL of 25% sodium methoxide inmethanol was added. The solvent was evaporated, and the residueevaporated from ether to give 0.54 g of the sodium salt of Enantiomer 2of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid as an off-white glass. MS (apci, pos) m/z=550. MS (apci, neg)m/z=548. ¹H NMR (400 MHz, D6 DMSO) δ 8.50 (t, 1H), 7.80 (d, 2H), 7.56(s, 1H), 7.14 (d, 1H), 7.07 (d, 2H), 6.53 (s, 1H), 4.23 (dt, 1H), 4.13(m, 1H), 3.79 (s, 3H), 3.38 (q, 2H), 3.29 (t, 1H), 3.17 (s, 2H), 2.21(m, 1H), 1.81 (m, 1H).

During the chiral separation described in Step C, fractions containingpeak 1 were collected to provide Enantiomer 1 of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=550. Chiral purity (ee) >98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material. The sodiumsalt of Enantiomer 1 was then prepared in a manner similar to thatprovided in Step D. MS (apci, pos) m/z=550. The sodium salt ofEnantiomer 1 was found to be less active than the sodium salt ofEnantiomer 2 when tested in an assay described in Example A.

EXAMPLE 237 Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Preparation of ethyl6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:To a suspension of 2-(4-chloro-2-methoxyphenyl)ethanamine hydrochloride(Preparation 8; 23.4 g, 105 mmol) in DCM (200 ml) was addedtriethylamine (16.8 ml, 120 mmol), and the mixture was allowed to stirfor 30 minutes (solids did not go into solution). To this was addedsequentially 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1; 37.8 g, 100 mmol, 1H-benzo[d][1,2,3]triazol-1-ol hydrate(15.4 g, 100 mmol), andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (23.1 g, 120 mmol), and the reaction was allowed to stirovernight (all solids went into solution after 2 hours). The reactionwas diluted with EtOAc (600 ml) and washed with 600 mL portions of 1MHCl, saturated aqueous bicarbonate, and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated. The residue wastaken up in hot ethyl acetate (500 ml) and was crystallized by theaddition of hexanes (1.5 L) to yield ethyl6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(51.1 g, 93.9 mmol).

Step B: Preparation of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: To a solution of ethyl6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(31.0 g, 56.9 mmol) in 3:1 THF/EtOH (200 ml) was added sodium hydroxide(120 ml, 120 mmol), and the reaction was allowed to stir overnight atambient temperature, at which point it was complete as determined bythin layer chromatography. The reaction was concentrated to about 25%volume, taken up in 100 ml of EtOH and 100 ml of water, and acidifiedwith 10 ml of concentrated HCl with stirring. The product initiallyoiled out, but became a solid. The solids were collected by filtrationand washed with 200 ml of water to yield6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (24.7 g, 47.8 mmol) as a white solid.

Step C: Isolation of Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The racemic mixture of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid was dissolved in methanol and resolved via supercritical fluidchromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting withmethanol/carbon dioxide at 100 bar, using 1 mL injections and a flowrate of 70 mL/min. Collection of fractions containing peak 2 and removalof volatiles provided Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=516. Chiral purity (ee) >98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material.

Step D: Preparation of the sodium salt of Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The material obtained above (peak 2; 32.4 g, 62.7 mmol) wassuspended in THF (55 ml) and EtOH (100 ml) was added followed by sodiummethanolate in methanol (125 ml, 62.7 mmol), and the reaction wasallowed to stir for 2 minutes, at which point it all crashed out ofsolution. The mixture was diluted with EtOH (300 ml), and wasconcentrated on the rotary evaporator. The residue was taken up in 500ml of EtOH and concentrated twice to remove any residual MeOH to give6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid, sodium salt of Enantiomer 2 as free flowing solid. MS (apci, pos)m/z=516. ¹H NMR (400 MHz, D6 DMSO) δ 8.42 (br s, 1H), 7.79 (m, 2H), 7.54(s, 1H), 7.14 (d, 1H), 7.02 (s, 1H), 6.91 (m, 3H), 6.51 (s, 1H), 4.20(m, 1H), 4.11 (m, 1H), 3.80 (s, 3H), 3.41 (m, 2H), 3.19 (m, 1H), 2.78(m, 2H), 2.19 (m, 1H), 1.76 (m, 1H). Optical rotation: [a]²⁵_(D)=−17.46° (c=1.00, MeOH).

During the chiral separation described in Step C, fractions containingpeak 1 were collected to provide Enantiomer 1 of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. MS (apci, pos) m/z=516. Chiral purity (ee) >98% as measured withCHIRALPAK® QD-AX column in comparison to racemic material. The sodiumsalt of Enantiomer 1 was then prepared in a manner similar to thatprovided in Step D. The sodium salt of Enantiomer 1 was found to be lessactive than the sodium salt of Enantiomer 2 when tested in an assaydescribed in Example A.

EXAMPLE 238 Enantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Preparation of ethyl6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate:A portion of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid(Preparation 1; 0.7 g, 1.86 mmol) was diluted with dichloromethane (1mL) followed by the addition of oxalyl chloride in dichloromethane (1.02ml, 2.04 mmol) and DMF (1 drop). After stirring for 10 minutes,2-(2-methoxy-4-(trifluoromethyl)phenyl)ethanamine (Preparation 9; 0.448g, 2.04 mmol) and DIEA (1.13 ml, 6.50 mmol) were added, and the reactionwas stirred for 2 hours. The reaction was loaded directly onto a biotage25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethylacetate/hexanes to yield ethyl6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(624 mg, 1.08 mmol, 58.1% yield).

Step B: Preparation of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Ethyl6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate(100 mg, 0.173 mmol) was diluted with tetrahydrofuran (1 mL) followed bythe addition of sodium hydroxide (692 μL of a 1 M aqueous solution,0.692 mmol) and ethanol (500 μL). After stirring for 2 hours, thereaction was diluted with ethyl acetate and 2N aqueous HCl. The layerswere separated and the organic layer was dried over MgSO₄, filtered andconcentrated. The material was purified using two 0.5 mm preparativesilica gel plates eluting with 10% methanol/dichloromethane to yield6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (61 mg, 0.111 mmol, 64.1% yield). ¹H NMR (400 MHz, D6 DMSO) δ 8.48(t, 1H), 7.82 (d, 2H), 7.44 (s, 1H), 7.35 (d, 1H), 7.23 (m, 2H), 6.96(d, 2H), 6.61 (s, 1H), 4.24 (m, 1H), 4.08 (m, 1H), 3.87 (s, 3H), 3.82(t, 1H), 3.47 (q, 1H), 3.17 (d, 1H), 2.89 (t, 2H), 2.21 (m, 1H), 2.05(m, 1H).

Step C: Isolation of Enantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The racemic mixture of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid was dissolved in methanol and resolved viasupercritical fluid chromatography employing a CHIRALCEL® OJ-H column(3×15 cm) eluting with methanol/carbon dioxide at 100 bar, using 1 mLinjections and a flow rate of 70 mL/min. Collection of fractionscontaining peak 2 and removal of volatiles provided Enantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. Chiral purity (ee) >98% as measured with CHIRALPAK® QD-AX columnin comparison to racemic material. ¹H NMR (400 MHz, D6 DMSO) δ 7.86 (m,2H), 7.51 (s, 1H), 7.42 (d, 1H), 7.19 (m, 2H), 6.78 (m, 2H), 6.36 (s,1H), 4.20 (dt, 1H), 4.09 (m, 1H), 3.86 (s, 3H), 3.36 (t, 2H), 3.21 (t,1H), 2.79 (t, 2H), 2.18 (m, 1H), 1.77 (m, 1H).

Step D: Preparation of the sodium salt of Enantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: Enantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (50 mg, 0.091 mmol) was diluted with THF (300μL) followed by the addition of sodium methoxide (182 μL, 0.091 mmol).After stirring for 1 hour, the reaction was concentrated and placedunder vacuum overnight. The residue was re-suspended in ethanol andconcentrated. The material was dried under vacuum at 60° C. for 5 hoursand then at ambient temperature overnight to yield the sodium salt ofEnantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid (40 mg, 0.073 mmol) as a white solid.

EXAMPLE 239 Enantiomer 2 of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid and preparation of sodium salt

Step A: Preparation of ethyl 6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate:4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation1; 9.099 ml, 3.185 mmol) in DMF was treated sequentially withN-ethyl-N-isopropylpropan-2-amine (0.8321 ml, 4.777 mmol),2-(2,4-dimethoxyphenyl)ethanamine hemisulfate (commercially availablefrom ChemBridge Corporation; 0.95 g; 2.07 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.7326 g, 3.822 mmol), and3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.1300 g, 0.9554 mmol) at ambienttemperature. The reaction was stirred for 14 hours. The reaction waspartitioned between ethyl acetate and brine, the organic layer dried invacuo, filtered, concentrated and purified on silica gel. Elution with20 to 75% ethyl acetate-hexanes provided ethyl6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(1.255 g, 2.324 mmol) as an off white solid.

Step B: Preparation of 6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Ethyl6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate(1.25 g, 2.31 mmol) in 2:1 THF-Ethanol (25 mL) was treated with sodiumhydroxide (9.26 ml, 9.26 mmol) at ambient temperature. After 3 hours,HPLC showed complete and clean conversion to a more polar peak. Thereaction was diluted with ethyl acetate and acidified with hydrogenchloride (9.72 ml, 9.72 mmol). Brine was added and the reactiontransferred to separatory funnel. The mixture was extracted with ethylacetate. The organic layer showed a single spot (10% MeOH in CHCl₃ witha few drops of AcOH). The ethyl acetate layer was dried over sodiumsulfate, filtered, and concentrated in vacuo to give 1.2 g of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid as a white solid. MS (apci, pos) m/z=512.

Step C: Isolation of Enantiomer 2 of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The racemic mixture of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid was dissolved in methanol and resolved via supercritical fluidchromatography employing a CHIRALCEL® OJ-H column (3×15 cm) and elutingwith methanol/carbon dioxide at 100 bar, using 1 mL injections and aflow rate of 70 mL/min. Collection of fractions containing peak 2 andremoval of volatiles provided Enantiomer 2 of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. Chiral purity (ee) >98% as measured with CHIRALPAK® QD-AX columnin comparison to racemic material.

Step D: Preparation of the sodium salt of Enantiomer 2 of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid: The material obtained above (peak 2; 32 mg, 0.063 mmol) wasdissolved in 3:1 THF-MeOH (2 ml total volume) was treated with sodiummethanolate, 0.5 M in MeOH (125 μL, 0.063 mmol) at ambient temperaturewith rapid stirring. After 10 minutes, the reaction was concentrated invacuo to a white semi-solid that was suspended in ethyl acetate andconcentrated to a white solid. The solids were suspended in ethanol, andthe suspension was concentrated in vacuo (4 torr on rotary evaporator at50° C.) and the resulting solids were dried under high vacuum for 24hours to give 33 mg of the sodium salt of Enantiomer 2 as a white solid.MS (apci, pos) m/z=512. MS (apci, neg) m/z=510.

During the chiral separation described in Step C, fractions containingpeak 1 were collected to provide Enantiomer 1 of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid. Chiral purity (ee) >98% as measured with CHIRALPAK® QD-AX columnin comparison to racemic material. The sodium of Enantiomer 1 was thenprepared in a manner similar to that described in Step D. MS (apci, pos)m/z=512. The sodium salt of Enantiomer 1 was found to be less activethan the sodium salt of Enantiomer 2 when tested in an assay describedin Example A.

1. A compound of general formula I:

or a salt thereof, wherein: A¹ is hydrogen, CN, Cl, F, Br, OMe, (1-4Calkyl) or cyclopropyl; A² is hydrogen, Cl, Br, F, (1-4C alkyl) orcyclopropyl; W is —C(═O)NR¹— or —NR²C(═O)—; R¹ and R² are each hydrogenor methyl; L is a bond, —(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*,(2-4C)alkenylene, —O(1-4C alkyl)-*, -(1-4C alkyl)-O—*, -(1-4Calkyl)-S—*, (3-6C)cycloalkylene, or hetCyc¹, wherein the * indicates thepoint of attachment to G, provided that when W is —NR²C(═O)— then L isnot —(CH═CH)—; m=0, 1 or 2; n=0 or 1; R^(a) and R^(b) are independentlyselected from hydrogen and (1-4C alkyl); R³ is hydrogen, (1-4C alkyl) orCH₂OH; R⁴ is hydrogen or methyl; R⁵ is hydrogen, (1-4C alkyl), OH,—O(1-4C alkyl) or F; R⁶ is hydrogen, F or methyl, or R⁵ and R⁶ togetherwith the carbon to which they are attached form a cyclopropyl ring;hetCyc¹ is a group having the formula

where t is 1 or 2 and p is 0 or 1, and the * indicates the point ofattachment to G; G is Ar¹, Ar², naphthyl, a benzo-fused (5-6C)cycloalkylring optionally substituted with one or more substituents independentlyselected from Cl and OMe, a benzo-fused 5-6 membered heterocyclic ringhaving 1-2 heteroatoms independently selected from O and N, a(3-6C)cycloalkyl ring optionally substituted with one or moresubstituents independently selected from (1-4C)alkyl, an oxaspirononanylring, or t-butyl; Ar¹ is phenyl optionally substituted with one or moresubstituents independently selected from F, Cl, Br, CF₃, (1-4C)alkyl,OH, —O(1-4C alkyl), —S(1-3C alkyl), —SCF₃, cyclopropyl, —CH₂N(1-3Calkyl)₂, —O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl—O-(1-3C)trifluoroalkyl, —OCH₂(cyclopropyl), and (3-4C)alkynyl; Ar² isphenyl which is substituted with Ar³, —O—Ar⁴, hetAr¹ or —O-hetAr²,wherein Ar² is optionally further substituted with one or moresubstituents independently selected from F, Cl and CF₃; Ar³ is phenyloptionally substituted with one or more substituents independentlyselected from F, Cl, Br and (1-4C alkyl); Ar⁴ is phenyl optionallysubstituted with one or more substituents independently selected from F,Cl, Br and (1-4C alkyl); hetAr¹ is a 6-membered heteroaryl having 1-2nitrogen atoms and optionally substituted with one or more substituentsindependently selected from (1-4C alkyl); hetAr² is a 6-memberedheteroaryl having 1-2 nitrogen atoms and optionally substituted with oneor more substituents independently selected from (1-4C alkyl) and CF₃;R^(7a), R^(7b) and R⁸ are each independently hydrogen or methyl; R⁹ ishydrogen, methyl, fluoro or NO₂; and R¹⁰ is hydrogen, methyl or fluoro.2. A compound of claim 1, where W is —C(═O)NR¹—.
 3. A compound of claim1, wherein: L is selected from a bond,—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, and (3-6C)cycloalkylene; and Gis selected from Ar¹, Ar² and a (3-6C)cycloalkyl ring.
 4. A compound ofclaim 3, wherein L is selected from a bond and—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*.
 5. A compound of claim 1,wherein L is selected from hetCyc¹, —O(1-4C alkyl)-*, -(1-4C alkyl)-O—*and -(1-4C alkyl)-S—*.
 6. A compound according to claim 1, wherein G isAr¹ or Ar²
 7. A compound according to claim 1, wherein: Ar¹ is phenyloptionally substituted with one or more substituents independentlyselected from F, Cl, Br, CF₃, methyl, ethyl, propyl, tert-butyl, OH,methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, SMe, SCF₃,cyclopropyl, CH₂NMe₂, OCH₂CH₂F, OCH₂CH₂CH₂F, OCHF₂, OCF₃,—OCH₂(cyclopropyl), and propynyl; Ar³ is selected from phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl,4-methylphenyl, 3,4-dimethylphenyl, and 2,3-dimethylphenyl; —O—Ar⁴ isselected from groups having the formula:

where X¹ and X² are independently selected from fluoro, chloro andbromo; hetAr¹ is selected from a pyridyl and pyrimidyl ring, each ofwhich is optionally substituted with one or more (1-4C alkyl) groups;and O-hetAr² is selected from pyridinyloxy and pyrimidinyloxy ring, eachof which is optionally substituted with CF₃.
 8. A compound according toclaim 1, wherein G is a (3-6C)cycloalkyl ring.
 9. A compound accordingto claim 1, wherein A¹ is selected from Cl, CN and cyclopropyl, and A²is selected from H, Cl and cyclopropyl.
 10. A compound according toclaim 9, wherein A¹ is CN, Cl or cyclopropyl.
 11. A compound accordingto claim 10, wherein A¹ is CN.
 12. A compound according to claim 10,wherein A¹ is Cl.
 13. A compound according to claim 10, wherein A² isselected from hydrogen and cyclopropyl.
 14. A compound according toclaim 1, wherein A¹ is CN, Cl, or cyclopropyl; A² is hydrogen, Cl, Br,or cyclopropyl; W is —C(═O)NH—; L is a bond or—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—; and G is Ar¹, Ar², naphthyl ora (3-6C)cycloalkyl ring optionally substituted with one or moresubstituents independently selected from (1-4C)alkyl.
 15. A compoundaccording to claim 13, wherein G is Ar¹, wherein Ar¹ is phenyloptionally substituted with one or more substituents independentlyselected from F, Cl, Br, CF₃, methyl, ethyl, propyl, tert-butyl, OH,methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, SMe, SCF₃,cyclopropyl, CH₂NMe₂, OCH₂CH₂F, OCH₂CH₂CH₂F, OCHF₂, OCF₃,—OCH₂(cyclopropyl), and propynyl.
 16. A compound of claim 15, wherein Lis a bond or CH₂CH₂.
 17. A compound of claim 16, wherein Ar¹ issubstituted with one to three of said substituents.
 18. A compoundaccording to claim 17, wherein R^(7a), R^(7b) and R⁸ are each hydrogen.19. A compound according to claim 18, wherein R⁹ and R¹⁹ are eachhydrogen.
 20. A pharmaceutical composition, which comprises a compoundof Formula I as defined in claim 1, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable diluent or carrier. 21.A method of treating an immunologic disorder in a mammal, whichcomprises administering to said mammal a therapeutically effectiveamount of a compound of Formula I as defined in claim 1, or apharmaceutically acceptable salt thereof.
 22. A compound of Formula I asdefined in claim 19, or a pharmaceutically acceptable salt thereof, forthe treatment of an immunologic disorder.
 23. A process for thepreparation of a compound of claim 1, which comprises: (a) for acompound of Formula I in which A¹ is CN and A² is hydrogen, reacting acorresponding compound having the formula (II):

in which P¹ represents a hydrogen atom or a carboxyl protecting groupand Z¹ represents a leaving atom or group, with a corresponding compoundhaving the formula (III)

in the presence of a base; or (b) coupling a compound of formula (IV)

in which P² is as defined for P¹ and Z² represents —NH₂ or —C(═O)OH, ora reactive derivative thereof, with a compound of formula (V)H—Z³-L-G  (V) in which Z³ represents OC(═O) or NH, respectively, or areactive derivative thereof; or (c) for a compound of Formula I in whichA¹ is Cl, (1-4C alkyl), OMe or cyclopropyl and A² is (1-4C alkyl),chloro, bromo or cyclopropyl, coupling a compound having the formula(VI)

in which P³ is as defined for P¹ and A¹ is Cl, (1-4C alkyl), orcyclopropyl, and A² is (1-4C alkyl), chloro, bromo or cyclopropyl, witha corresponding compound having the formula (VII)

wherein E is an electron withdrawing group and Z⁴ is a leaving atom, inthe presence of a base, and if desired removing said electronwithdrawing group; or (d) for a compound of Formula I where G is Ar^(x)where Ar^(x) is (1) Ar¹ substituted with cyclopropyl or (1-4C)alkyl andoptionally further substituted as defined for Ar¹, or (2) Ar² where Ar²is phenyl substituted with Ar³ and optionally further substituted with For Cl, reacting a corresponding compound having the formula (VIII)

where P⁴ is as defined for P¹ and Z⁵ is a leaving atom or group, with acompound having the formula Y—B(OH)₂ where Y is cyclopropyl, (1-4Calkyl) or Ar³, in the presence of a transition metal catalyst and aligand; or (e) for a compound of Formula I where L is a bond and G isAr¹ or Ar², reacting a corresponding compound having the formula (IX)

wherein P⁵ is as defined for P¹, with a compound having the formulaAr¹—Z⁶ or Ar²—Z⁶ where Z⁶ is a leaving atom or group, in the presence ofa metal catalyst and a ligand; or (f) for a compound of Formula I whereA¹ is chloro, A² is cyclopropyl, R⁹ and R¹⁰ are hydrogen, and W isC(═OH)NH, reacting a corresponding compound having the formula (X)

wherein P⁶ is as defined for P¹, E is an electron withdrawing group, andB is O-tertbutyl, NH₂ or NH-L-G, with about 2 equivalents ofcyclopropylboronic acid in the presence of a suitable base, a metalcatalyst and a ligand at temperatures between about 100° C. and about150° C., followed by removal of the electron withdrawing group, ifdesired, and coupling with a compound having the formula H₂N-L-G when Bis O-tBu or coupling with a compound having the formula X-L-G when B isNH₂, where X is a leaving group or atom; or (g) for a compound ofFormula I where A¹ is cyclopropyl, A² is cyclopropyl, R⁹ and R¹⁰ arehydrogen and W is C(═O)NH, reacting a corresponding compound having theformula (X) with about 4 equivalents of cyclopropylboronic acid in thepresence of a suitable base, a metal catalyst and a ligand attemperatures between about 100° C. and 150° C., followed by removal ofthe electron withdrawing group, if desired, and coupling with a compoundhaving the formula H₂N-L-G when B is O-tBu or coupling with a compoundhaving the formula X-L-G when B is NH₂, where X is a leaving group oratom; or (h) for a compound of Formula I where A¹ is cyclopropyl, A² ishydrogen, R⁹ and R¹⁰ are hydrogen and W is C(═O)NH, reacting acorresponding compound having the formula (XI)

with about 3 equivalents of cyclopropylboronic acid in the presence of asuitable base, a metal catalyst and a ligand at temperatures betweenabout 90° C. and 150° C., for example 120° C., followed by removal ofthe electron withdrawing group, if desired, and coupling with a compoundhaving the formula H₂N-L-G when B is O-tBu or coupling with a compoundhaving the formula X-L-G when B is NH₂, where X is a leaving group oratom; and removing any protecting group or groups and, if desired,forming a salt.
 24. A compound of general formula Ie:

or a salt thereof, wherein: Pg is a carboxyl protecting group; A¹ ishydrogen, CN, Cl, F, Br, OMe, (1-4C alkyl) or cyclopropyl; A² ishydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl; W is —C(═O)NR¹— or—NR²C(═O)—; R¹ and R² are each hydrogen or methyl; L is a bond,—(CR³R⁴)_(n)—(CR^(a)R^(b))_(m)—(CR⁵R⁶)—*, (2-4C)alkenylene, —O(1-4Calkyl)-*, -(1-4C alkyl)-O—*, -(1-4C alkyl)-S—*, (3-6C)cycloalkylene, orhetCyc¹, wherein the * indicates the point of attachment to G, providedthat when W is —NR²C(═O)— then L is not —(CH═CH)—; m=0, 1 or 2; n=0 or1; R^(a) and R^(b) are independently selected from hydrogen and (1-4Calkyl); R³ is hydrogen, (1-4C alkyl) or CH₂OH; R⁴ is hydrogen or methyl;R⁵ is hydrogen, (1-4C alkyl), OH, —O(1-4C alkyl) or F; R⁶ is hydrogen, For methyl, or R⁵ and R⁶ together with the carbon to which they areattached form a cyclopropyl ring; hetCyc¹ is a group having the formula

where t is 1 or 2 and p is 0 or 1, and the * indicates the point ofattachment to G; G is Ar¹, Ar², naphthyl, a benzo-fused (5-6C)cycloalkylring optionally substituted with one or more substituents independentlyselected from Cl and OMe, a benzo-fused 5-6 membered heterocyclic ringhaving 1-2 heteroatoms independently selected from O and N, a(3-6C)cycloalkyl ring optionally substituted with one or moresubstituents independently selected from (1-4C)alkyl, an oxaspirononanylring, or t-butyl; Ar¹ is phenyl optionally substituted with one or moresubstituents independently selected from F, Cl, Br, CF₃, (1-4C)alkyl,OH, —O(1-4C alkyl), —S(1-3C alkyl), —SCF₃, cyclopropyl, —CH₂N(1-3Calkyl)₂, —O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl—O-(1-3C)trifluoroalkyl, —OCH₂(cyclopropyl), and (3-4C)alkynyl; Ar² isphenyl which is substituted with Ar³, —O—Ar⁴, hetAr¹ or —O-hetAr²,wherein Ar² is optionally further substituted with one or moresubstituents independently selected from F, Cl and CF₃; Ar³ is phenyloptionally substituted with one or more substituents independentlyselected from F, Cl, Br and (1-4C alkyl); Ar⁴ is phenyl optionallysubstituted with one or more substituents independently selected from F,Cl, Br and (1-4C alkyl); hetAr¹ is a 6-membered heteroaryl having 1-2nitrogen atoms and optionally substituted with one or more substituentsindependently selected from (1-4C alkyl); hetAr² is a 6-memberedheteroaryl having 1-2 nitrogen atoms and optionally substituted with oneor more substituents independently selected from (1-4C alkyl) and CF₃;R^(7a), R^(7b) and R⁸ are each independently hydrogen or methyl; R⁹ ishydrogen, methyl, fluoro or NO₂; and R¹⁰ is hydrogen, methyl or fluoro.25. A compound of claim 1, which is in the acid form.
 26. A compound ofclaim 1, which is a sodium salt.
 27. A compound of Formula I selectedfrom 6-Cyano-7-(4-(4-chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-chlorophenylcarbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylicacid;7-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylicacid;6-Cyano-7-(4-(2,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylicacid; 6-Cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-Chlorobenzyloxycarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;6-Cyano-7-(4-(3,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-nitrophenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; 6-chloro-7-(4-(4-phenylbutylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(3-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(4-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylicacid;(Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylicacid;(Z)-6-chloro-7-(4-(4-(2,4-dichlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(2,4-dichlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dimethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-cyclopropylethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2-(2′,3-dichlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(3-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2-(2′,5-dichlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;8-bromo-6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6,8-dicyclopropylchroman-4-carboxylicacid;6,8-dicyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6-cyclopropylchroman-4-carboxylicacid;6-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-8-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid6-Cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-((2-Phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid;7-(4-((3-Methoxyphenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid;7-(4-((4-Fluorophenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid;7-(4-((4-(Trifluoromethyl)phenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid;7-(4-((2-(4-Chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylicacid; 7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;6-Cyano-7-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(naphthalen-1-ylmethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-tert-Butylphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;7-(4-(2-Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid; 7-(4-(Biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid; 7-(4-(Biphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;7-(4-(4′-Chlorobiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;6-Cyano-7-(4-(3-(2-methylpyrimidin-4-yl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(4′-chloro-6-fluorobiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(5-Chloro-2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid; 7-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;6-Cyano-7-(4-(4-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(naphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-difluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-6-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,5-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,3-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(5-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(3′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-fluoro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(5-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(4′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(3′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(p-tolylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2-chlorophenoxy)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(2-tert-butoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(3-chlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)azetidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(2,4-dichlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-((S)-1-(3-chlorophenyl)piperidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-tert-Butylcyclohexylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid; 7-(4-(4-Chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;7-(4-(4-Chlorophenethylcarbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylicacid;6-Cyano-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(1-(4-Chlorophenyl)propan-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;7-(4-(4-Chloro-3-methoxyphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;7-(4-(3-tert-Butylphenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;6-Cyano-7-(4-(3-isopropoxyphenylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,3-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-tert-butylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(3-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylicacid;Cis-6-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;Trans-6-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-Chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-(3-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-(4-methylphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-(4-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-(4-(methylthio)phenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-(3-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-phenylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-p-tolylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(3-(3-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(4-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(3-methylphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(3-(trifluoromethyl)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(3-fluorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(3-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(3,4-dichlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(4-methoxyphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-(4-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,3-dimethylbutylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-cyclohexylethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-3-methylphenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-cyclopentylethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(1-oxaspiro[4.4]nonan-3-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,5-dimethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3-chloro-2-methoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(trifluoro-methyl)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(2-(benzo[d][1,3]dioxol-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenyl)-2,2-difluoroethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-ethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-ethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(cyclopropyl-methoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(2-methoxyethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4,5-dichloro-2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-isopropoxy-phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(3,5-dichlorophen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(4-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-phenoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(4-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(3-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(3-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(3,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-(2,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(2-fluoroethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(3-fluoropropoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-6-methoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,6-dimethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;5-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-((1-(4-chlorophenyl)cyclopropyl)methylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylicacid;6-chloro-7-(4-(2-phenoxyethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;7-(4-(2,4-bis(trifluoromethyl)phenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylicacid;6-chloro-7-(4-(2,4,6-trimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-(difluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,6-dichloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2,4-diethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-chloro-4,6-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-ethoxy-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-ethoxy-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(4-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-((5-chloro-2,3-dihydro-1H-inden-1-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-cyclopropyl-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-Chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid;6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylicacid; Enantiomer 2 of6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylicacid; and pharmaceutically acceptable salts thereof.
 28. A compound ofclaim 27, wherein the compound is a sodium salt.